EP2331502A2

EP2331502A2 - Compounds for the treatment of hepatitis c

Info

Publication number: EP2331502A2
Application number: EP09792143A
Authority: EP
Inventors: Richard Pracitto; John F. Kadow; John A. Bender; Brett R. Beno; Katharine A. Grant-Young; Ying Han; Piyasena Hewawasam; Andrew Nickel; Kyle E. Parcella; Kap-Sun Yeung; Louis S. Chupak
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2008-09-11
Filing date: 2009-09-02
Publication date: 2011-06-15
Anticipated expiration: 2029-09-02
Also published as: US8198449B2; AR073586A1; TW201014855A; WO2010030538A2; KR20110056537A; US20120232099A1; EP2331502B1; US8536338B2; WO2010030538A3; CN102209711B; MX2011002471A; CN102209711A; AU2009291993A1; JP2012502099A; US20100063068A1; CN103864783A

Abstract

The disclosure provides compounds of formula I, II, III, IV, and V, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

Description

COMPOUNDS FOR THE TREATMENT OF HEPATITIS C

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application serial number 61/096004 filed September 11, 2008.

BACKGROUND OF THE INVENTION

The disclosure generally relates to the novel compounds of formula I, II, III,

IV, and. V, including their salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV. The disclosure also relates to compositions and methods of using these compounds.

Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated

170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer_s G. M.; Walker, B. D. N. Engl J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5 '-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus- specific proteins via translation of a single, uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins, In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N- terminal region of NS3 (also referred to as NS 3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS 3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components, The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV. The HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides (Bressanelli; S. et al., Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242.

Currently, the most effective HCV therapy employs a combination of alpha- interferon and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al, Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N, Engl. J. Med. 2000, 343, 1666-1672). However, even with experimental therapeutic regimens involving combinations of pegylated alpha- interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and important need to develop effective therapeutics for treatment of HCV infection. HCV-796, an HCV NS5B inhibitor, showed an ability to reduce HCV RNA levels in patients. The viral RNA levels decreased transiently and then rebounded during dosing when treatment was with the compound as a single agent but levels dropped more robustly when combined with the standard of care which is a form of interferon and ribavirin. The development of this compound was suspended due to hepatic toxicity observed during exteneded dosing of the combination regimens. US patent 7,265,152 and the corresponding PCT patent application WO2004/041201A2 describe compounds of the HCV-796 class.

The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I, II, III, IV, or V

Jj

where:

R¹ is halo, alkyl, cycloalkyl, alkoxy, oxazolidinonyl, dioxothiazinyl, R⁵R⁶N,

CONR⁷R⁸ _} piperidinonyl substituted with 1 * ^Al"1 substitαent, pyrrolyl

R⁹ R¹⁰ substituted with 1 ^{* Ar1} substituent, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents;

R² is hydrogen, halo, alkyl, cycloalkyl, alkoxy, or R⁵R⁶N;

R³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, C0NR^πR¹², (R¹³)(R¹⁴)NCONH, triazolyl, thiazolyl, or tetrazolyl;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, benzyl, alkylcarbonyl, haloalkylcarbonyl, phenylcarbonyl, (alkoxyρhenyl)carbonyl_s alkylsulfonyl, phenylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl; R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

or R⁵ and R⁶ taken together with the nitrogen to which they are attached is oxazolidinonyl or dioxothiazinyl;

R⁹ R¹⁰ R¹* R¹⁰ R⁷ is hydrogen, alkyl, *^R¹⁵ , _or * ^Ar1 ;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen or alkyl;

Rⁱ⁰ is hydrogen or alkyl;

or R⁹ and R^ϊ0 taken together is ethylene, propylene, butylene, or pentylene;

R ■ 11 is hydrogen or alkyl;

R¹² is hydrogen or alkyl;

or R¹ ' and R^ιz taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R¹³ is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

or R¹³ and R¹⁴ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R¹⁵ is alkyl or cycloalkyl;

R¹⁶ is hydrogen, halo, alkyl, or alkoxy; R¹⁷ is hydrogen, halo, alkyl, or alkoxy; and

Ar¹ is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo, alkyl, or phenyl substituents;

or a pharmaceutically acceptable salt therof.

Another aspect of the invention is a compound of formula I, II, III, IV, or V where

R¹ is halo, alkoxy, oxazolidinonyl, dioxothiazinyl, R⁵R⁶N, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR⁷R⁸, and where said phenyl is substituted with 0-1 alkyl substituents;

R² is hydrogen, halo, alkoxy, or R⁵R⁶N;

R³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR¹¹R¹², (R¹³)(R¹⁴)NCONH, triazolyl, thiazolyl, or tetrazolyl;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is alkylsulfonyl;

R⁶ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

R⁹ R¹⁰

R⁷ is hydrogen, alkyl, or ^{* Ar1} ;

R⁸ is hydrogen or alkyl;

R⁹ is hydrogen or alkyl; R¹⁰ is hydrogen or alkyl;

or R⁹ and R¹⁰ taken together is ethylene, propylene, butylene, or pentylene;

R^u is hydrogen or alkyl;

R¹² is hydrogen or alkyl;

R^B is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

R¹⁵ is hydrogen;

R ⁷ is hydrogen; and

Ar¹ is phenyl or pyridinyl;

or a pharmaceutically acceptable salt therof.

R¹ is alkoxy or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, and CONR⁷R^S, and where said phenyl is also substituted with 0-2 alkyl substituents;

R² is hydrogen, halo or R⁵R⁶N;

R³ is CONR¹³R¹⁴; R⁴ is phenyl substituted with 0-2 halo;

R^s is alkylsulfonyl;

R^δ is hydrogen or hydroxyalkyl;

R⁹ R^w

R⁷ is hydrogen, alkyl, or ^{* Af1}

R is hydrogen;

R⁹ is alkyl;

R¹⁰ is alkyl;

or R⁹ and R^!0 taken together is ethylene or propylene;

R¹ ' is hydrogen or alkyl;

R¹² is hydrogen or alkyl;

Rⁱ³ is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

R¹⁶ is hydrogen;

R¹⁷ is hydrogen; and

Ar¹ is pyridinyl or phenyl, and is substituted with 0-1 alkyl or phenyl substituents; or a pharmaceutically acceptable salt therof.

R¹ is cycloalkyl, alkoxy, CONR⁷R⁸ ₁ piperidinonyl substituted with 1

* ^Af1 substituent, pyrrolyl substituted with 1 * ^Al"1 substituent, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, carboxy, and CONR R , and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents;

R² is hydrogen, halo, cycloalkyl, or R⁵R⁶N;

R³ is CONRⁿR¹²;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is hydrogen, (cycloalkyl)alkyl, benzyl, haloalkylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl;

R⁶ is hydrogen or hydroxyalkyl;

R® R¹⁰ R⁹ R¹⁰

R⁷ is hydrogen, alkyl, ^{* Ri5} , or ^{* Ar1} ;

R^s is hydrogen;

R⁹ is alkyl;

R¹⁰ is alkyl; or R⁹ and R¹⁰ taken together is ethylene or propylene;

Rⁿ is alkyl;

R¹² is hydrogen;

R¹⁵ is alkyl or cycloalkyl;

R¹⁶ is hydrogen;

R¹⁷ is hydrogen; and

Ar¹ is isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 alkyl or phenyl substituents;

or a pharmaceutically acceptable salt therof.

Another aspect of the invention is a compound of formula Ia, Ha, Ilia, IVa, or Va where

where:

R¹ is halo, alkoxy, oxazolidinonyl, dioxothiazinyl, R⁵R⁶N, or phenyl where phenyl is substituted with 1-2 substituents selected from the group consisting of allcyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR⁷R⁸, and where phenyl is substituted with 0-1 alkyl substituent;

R² is hydrogen, halo, alkoxy, or R⁵R⁶N;

R³ is cyano, alkoxycarbonyl, (cycloalkyljoxycarbonyl, (alkylsulfonyl)aminooarbonyl, CONR¹¹R¹², (R¹³)(R^M)NCONH, triazolyl, thiazolyl, or tetrazolyl;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is alkylsulfonyl;

R⁶ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

R⁹ R¹⁰

R⁷ is hydrogen, alkyl, or ^*■ Ar¹ ;

R is hydrogen or alkyl;

R⁹ is hydrogen or alkyl; R¹⁰ is hydrogen or alkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen or alkyl;

or R¹¹ and R¹² taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and

R¹³ is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

or R¹³ and R^H taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and

Ar¹ is phenyl or pyridinyl;

or a pharmaceutically acceptable salt therof.

Another aspect of the invention is a compound of formula Ia where R¹⁶ and R^π are hydrogen.

Another aspect of the invention is a compound of formula Ha where R¹⁶ and R^π are hydrogen.

Another aspect of the invention is a compound of formula Ilia where R and R^ϊ7 are hydrogen.

Another aspect of the invention is a compound of formula IVa where R^lfi and

R^!7 are hydrogen.

Another aspect of the invention is a compound of formula Va where R¹⁶ and

R .17 are hydrogen.

Another aspect of the invention is a compound of formula I, II, III, IV, or V where R¹ is phenyl substituted with 1 CONR⁷R⁸ substituent and 0-2 halo, alkyl, or alkoxy substituents; R² is hydrogen, halo, alkyl, or R⁵R⁶N; R³ is CONRⁿR¹²; R⁴ is

_Ri i _Rio monoflurophenyl; R⁵ is alkylsulfonyl; R⁶ is alkyl; R⁷ is ^{* Ar1} ; R⁸ is hydrogen; R⁹ is methyl; R¹⁰ is methyl; or R⁹ and R¹⁰ taken together is ethylene; R¹ ' is alkyl; R¹² is hydrogen or alkyl; R¹⁶ is hydrogen; R¹⁷ is hydrogen; and Ar¹ is oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo or alkyl substituents; or a pharmaceutically acceptable salt therof. Another aspect of the invention is a compound of formula I, II, III, IV, or V where R¹ is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carbosy, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents.

Another aspect of the invention is a compound of formula I, II, III, IV, or V where R¹ is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR⁷R⁸, and where said phenyl is substituted with 0-1 halo, alkyl, or alkoxy substituents;

Another aspect of the invention is a compound of formula I, II, III, IV, or V where R² is R⁵R⁶N;

Another aspect of the invention is a compound of formula I, II, III, IV, or V where R³ is CONR¹¹R¹².

Another aspect of the invention is a compound of formula I, II, III, IV, or V where R⁴ is phenyl or monofluorophenyl.

Another aspect of the invention is a compound of formula I, II, III, IV, or V where Ar¹ is phenyl.

Any scope of any variable, including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^π, R¹² ₅ R¹³, R¹⁴, R⁵⁵, R¹⁶, R¹⁷, or Ar¹ can be used independently with the scope of any other instance of a variable.

Unless specified otherwise, these terms have the following meanings. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Hydroxyalkyl," "alkoxy" and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. "Aryl" includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system (for example a bicyclic ring system) are intended to bond to the ring where they are drawn to append. For example, substituents R¹ and R² of formula IV are intended to bond to the benzene ring of formula IV and not to the thiophene ring.

Ethylene means ethanediyl or -CH₂CH₂-; propylene means propanediyl or -CH2CH2CH2-; butylene means butanediyl or -CH₂CH₂CH₂CH₂-; pentylene means pentanediyl or -CH₂CH₂CH₂CH₂CH₂-.

Dioxothiazinyl means

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylarmne, piperazine, potassium, sodium, tromethamine, and zinc. Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, the structures below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.

The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ^!4C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity, In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for N₅N- dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride; "BOC", "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "mm" for minutes; ¹¹EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et₂O" for diethyl ether; "DMAP" for 4-dimethylarninopyridine; "DCE" for 1,2-dicMoroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1- hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf for CF₃(CF₂J₃SO₂S and "TMOF" for trimethylorthoformate,

As shown in Scheme 1, some compounds of the invention may be prepared by coupling an aryl trifiate or halide to a substituted phenyl boronic acid that in some examples contains a carboxylic acid or carboxylic acid ester. Other coupling partner, techniques and conditions are known in the art as are other carbon-carbon bond forming reactions. Acids and esters may be converted to amides by methods known in the art.

DIEA Bis-sulfonamides may be selectively hydrolyzed to a monosulfonamide. The monosulfonamide may be alkylated again with either a simple or functionalized alkyl.

Scheme 2.

Scheme 3.

1) ami nation

Scheme 3 cont.

Scheme 3 cont,

Pd(OAc)₂_

Scheme 4,

THF

Scheme 5.

Scheme 6.

Br

Scheme 7,

Scheme 8.

dioxaπe/water 5:1 , 7h, 95⁰C

Scheme 9.

N

reflux

OXONE, DMF, rt

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined in the following HCV RdRp assays.

HCVNS5B RdRp cloning, expression, and purification. The cDNA encoding the NS5B protein of HCV, genotype Ib, was cloned into the ρET21a expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility. The E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 ⁰C for ~ 4 hours until the cultures reached an optical density of 2,0 at 600 nm. The cultures were cooled to 20 ⁰C and induced with 1 mM IPTG. Fresh ampicillin was added to a final concentration of 50 μg/ml and the cells were grown overnight at 20 ⁰C.

Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% triton X-100, 1 mM DTT, ImM EDTA, 20% glycerol, 0.5 mg/ml lysozyme, 10 mM MgC12, 15 ug/ml deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer. To reduce the viscosity of the sample, aliquots of the lysate were sonicated on. ice using a microtip attached to a Branson sonicator. The sonicated lysate was centrifuged at 100,000 x g for lhr at 4 ⁰C and filtered through a 0.2 μm filter unit (Corning).

The protein was purified using three sequential chromatography steps: Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose (Pharmacia). The chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgCl 2 or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for charging the protein onto the column. Each column was eluted with a NaCl gradient which varied in length from 5-50 column volumes depending on the column type. After the final chromatography step, the resulting purity of the enzyme is >90% based on SDS-PAGE analysis. The enzyme was aliquoted and stored at -80 ⁰C.

Standard HCV NS5B RdRp enzyme assay. HCV RdRp genotype Ib assays were run in a final volume of 60 μl in 96 well plates (Costar 3912). The assay buffer is composed of 20 mM Hepes, pH 7.5, 2,5 mM KCl₅ 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. AU compounds were serially diluted (3-fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%. HCV RdRp genotype Ib enzyme was used at a final concentration of 28 nM. A polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27- 4110). Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 μCi (0.29 μM total UTP). Reactions were initiated by the addition of enzyme, incubated at 30 ⁰C for 60 min, and stopped by adding 25 μl of 50 mM EDTA containing SPA beads (4 μg/μl, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXT after >lhr incubation at room temperature.

Modified HCVNS5B RdRp enzyme assay. A modified enzyme assay was performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin- coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 μg/μl beads. Order of addition in the assay: enzyme (14 nM) was added to diluted compound followed by the addition of a mixture of template (0.2 nM) , 3H-UTP (0.6 μCi, 0.29 μM), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 30° C.

IC₅₀ values for compounds were determined using seven different [I]. IC₅₀ values were calculated from the inhibition using the formula y = A+((B- A)/(1+((C/_X)^ΛD))).

FRET Assay Preparation. To perform the HCV FRET screening assay, 96- welϊ cell culture plates were used. The FRET peptide (Anaspec, Inc.) (Taliani et al., Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor DABCYL, near the other end. The fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent. The assay reagent was made as follows: 5X cell Luciferase cell culture lysis reagent from Promega (#E153A) diluted to IX with dE^O, NaCl added to 150 mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with titrated test compounds added in columns 3 through 12; columns ϊ and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound. The plates were then placed in a CO₂ incubator at 37 ⁰C,

Assays. Subsequent to addition of the test compounds described above

(FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity. After reading in a Cytoflour 4000 instrument (PE Biosystems), plates were rinsed with PBS and then used for FRET assay by the addition of 30 ul of the FRET peptide assay reagent described above (FRET Assay Preparation) per well. The plate was then placed into the Cytoflour 4000 instrument which had been set to 340 excite/490 emission, automatic mode for 20 cycles and the plate read in a kinetic mode. Typically, the signal to noise using an endpoint analysis after the reads was at least three- fold. Alternatively, after Alamar blue reading, plates were rinsed with PBS, 50 ul of DMEM (high glucose) without phenol red was added and plates were then used for luciferase assay using the Promega Dual-Glo Luciferase Assay System.

Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values. To calculate cytoxicity values, the average Alamar Blue fluorescence signals from the control wells were set as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity. To calculate the HCV replicon inhibition values, an average background value was obtained from the two wells containing the highest amount of HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naϊve Huh-7 cells.

The background numbers were then subtracted from the average signal obtained from the control wells and this number was used as 100% activity. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. EC₅₀ values for a protease inhibitor titration were calculated as the concentration which caused a 50% reduction in FRET or luciferase activity. The two numbers generated for the compound plate, percent cytoxicity and percent activity were used to determine compounds of interest for further analysis.

HCV Replicon Luciferase Reporter Assay

The HCV replicon luciferase assay was developed to monitor the inhibitory effects of compounds described in the disclosure on HCV viral replication. Utilization of a replicon luciferase reporter assay was first described by Krieger et al (Krieger N, Lohmann V, and Bartenschlager R, J. Virol 75(10):4614-4624 (2001)). HUH-7 cells, constitutively expressing the HCV replicon, were grown in Dulbecco's Modified Eagle Media (DMEM) (Gibco-BRL) containing 10% Fetal calf serum (FCS) (Sigma) and 1 mg/ml G418 (Gibco-BRL). Compounds were serially diluted 3 folds in DMSO for a twenty-point titration and subsequently transferred to sterile 384-well tissue-culture treated plates (Corning cat # 3571). The plates were then seeded with 50 μl of cells at a density of 3.0 x 10³ cells/well in DMEM containing 4 % FCS (final DMSO concentration at 0.5 %). After 3 days incubation at 37°C, cells were analyzed for Renilla Luciferase activity using the EnduRen as substrate (Promega cat #E6485). The EnduRen substrate was diluted in DMEM and then added to the plates to a final concentration of 7.5 μM. The plates were incubated for 2 hrs at 37°C and then read immediately for 30 seconds with Viewlux Imager (PerkinElmer) using a luminescence program. To assess cytotoxicity of compounds, CC₅₀ values were generated by multiplexing the EnduRen-containing plates with Cell Titer-Blue (Promega, cat # G8082). 3 μl of Cell-Titer Blue was added to each well and incubated for 8 hrs at 37°C. The fluorescence signal from each well was read, with an excitation wavelength at 525/10 nm and an emission wavelength of 598/10 nm, using the Viewlux Imager.

Representative data for compounds are reported in Tables 1 and 2. Table 1.

10.0 μM; D >0.67 μM but an exact value was not determined; E >10.0 μM; F >0.4 μM; but an exact value was not determined; G > 1.39 μM but an exact value was not determined; H >0.62 μM but an exact value was not determined; I >4 μM but an exact value was not determined; J>3.7 μM but an exact value was not determined; K >1.23 μM but an exact value was not determined; L >4.17 μM but an exact value was not determined; M > 0.5 μM but an exact value was not determined. *EC50 determined using the 384 well plate protocol

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'- monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metallopro tease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

"Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.

"Patient" means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

"Treatment," "therapy," "regimen," "HCV infection," and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical j udgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of 1 - 100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods are listed in Table 2.

Table 2.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and Examples are defined as follows: "NaHMDS" for sodium bis(trimethylsilyl)amide; "DMF" for N,N- dimethylformamide; "MeOH" for methanol; "NBS" for N-bromosuccinimide; "Ar" for aryl; "TFA" for trifluoroacetic acid; "LAH" for lithium aluminum hydride; "BOC", "DMSO" for dimethylsulfoxide; "h" for hours; "rt" for room temperature or retention time (context will dictate); "min" for minutes; "EtOAc" for ethyl acetate; "THF" for tetrahydrofuran; "EDTA" for ethylenediaminetetraacetic acid; "Et₂O" for diethyl ether; "DMAP" for 4-dimethylammoρyridine; "DCE" for 1,2-dichloroethane; "ACN" for acetonitrile; "DME" for 1,2-dimethoxyethane; "HOBt" for 1- hydroxybenzotriazole hydrate; "DIEA" for diisopropylethylamine, "Nf for CF₃(CF₃)SSO₂-; and "TMOF" for trimethylorthoformate.

Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "⁰C" for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "μL" for microliter or microliters, "N" for normal, "M" for molar, "rnmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "cone," for concentrate, "sat" or "sat'd " for saturated, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry , "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tic" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "^lH" for proton, "δ" for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and ^«α'\ "β", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art.

3-(3-nitropyridin-4-yI)benzoic acid. To a degassed mixture containing 4-chloro-3- nitropyridine (3.0 g, 18.9 rnmol), 3-boronobenzoic acid (3.7 g, 22.7 mmol), potassium carbonate (5.2 g, 37.8 mmol) and dioxane (189 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.30 g, 0.28 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 100° C for 15 h, cooled to room temperature, filtered and concentrated to afford 3-(3-nitropyridin-4- yl)benzoic acid as a tan residue which was used without further purification. LCMS: retention time; 1.375 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Sunfire, 5u, C 18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 iiM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 245 (MH⁺).

3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide. To a solution containing 2-phenylpropan-2-amine (5.5 g, 40.4 mmol), diisopropylethylamine (18.8 niL, 108 mmol), 3-(3-nitropyridin-4-yl)benzoic acid (8.8 g, 27.0 mmol) and DMF (180 mL) was added HATU (15.4 g, 40.4 mmol) in one portion. The solution was maintained at room temperature for Ih then concentrated. Purification on silica gel (50-100% ethyl acetate/hexanes, 60 min. gradient) afforded 3-(3-nitropyridin-4-yl)~ N-(2-phenylpropan-2-yi)benzamide as a dark yellow, fluffy solid. IH NMR (400 MHz, DMSO-D6) δ ppm 9.21 (s, 1 H), 8.93 (d, J=5.02 Hz, 1 H), 8.51 (s, 1 H), 7.97 (dt, /=7.03, 1.76 Hz, 1 H)₅ 7.92 (s, 1 H)₅ 7.73 (d, /=5.02 Hz, 1 H), 7.52 - 7.61 (m, 2 H), 7.34 - 7.41 (m, 2 H), 7.27 (t, /=7.65 Hz, 2 H), 7.16 (t, /=7.28 Hz, 1 H), 1.64 - 1.72 (m, 6 H). LCMS: retention time: 2.060 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C 18, 3.0 x 50 mm column using a SPD-I OAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 362 (MH⁺).

3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide. To a solution containing 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (2.0 g, 5.5 mmol) and methanol (18.5 mL) was added 10% Pd/C (1.6 g, 0.76 mmol, wet, 50% water) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan~2-yl)benzamide as a pale yellow oil which was used without further purification. IH NMR (400 MHz, DMSO-D 6) 6 ppm 8.47 (s, 1 H), 8.11 (s, 1 H), 7.93 (s, 1 H), 7.85 (d, J=4.77 Hz, 1 H), 7.81 (ddd, J=7.65, 1.63, 1.51 Hz, 1 H), 7.52 - 7.61 (m, 2 H), 7.36 - 7.41 (m, 2 H), 7.24 - 7.30 (m, 2 H), 7.15 (t, J=7.28 Hz, 1 H), 7.04 (d, J-5.02 Hz, 1 H), 5.15 (s, 2 H)₅ 1.64 - 1.70 (m, 6 H). LCMS: retention time: 1.240 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 ffiM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 332 (MH^4").

3-(3-(methyliSuIfonainido)pyrldin-4-yl)-N-(2-phenylpropan-2-yl)benzamide, To a solution containing 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (1.7 g, 5.1 mmol), triethylamine (5.2 g, 51.3 mmol), and dichloromethane (85 mL) was added methanesufonylchloride (0.90 mL, 11.3 mmol) in dichloromethane (75 mL) dropwise over 3 min. The solution was maintained at room temperature for Ih and concentrated to remove all solvent. The residue thus obtained was dissolved in THF (51 mL) and tetrabutylammoniumfluoride (24 mL, 1.0 M in THF) was added in a steady stream via syringe. The solution was maintained at 60° C for 18 h, concentrated and dissolved in ethyl acetate (75 mL). The solution was washed with water (5 x 50 mL), washed with brine (50 mL), dried over MgSO4, filtered and concentrated. Purification on silica gel (0-8% methanol/dichloromethane, 60 min gradient) afforded 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropaii-2- yl)benzamide as a pale yellow foam. IH NMR (500 MHz, DMSO-D6) δ ppm 9.42 (s, 1 H), 8.64 (s, 1 H), 8.56 (d, /=4.88 Hz, 1 H), 8.45 (s, 1 H), 8.03 (s, 1 H), 7.90 (d, /=7.63 Hz, 1 H), 7.71 (d, /=7.63 Hz, 1 H), 7.58 (t, /=7.78 Hz, 1 H), 7.49 (d, /=4.88 Hz, 1 H), 7.40 (d, /=7.93 Hz, 2 H), 7.29 (t, J=7.63 Hz, 2 H), 7.17 (t, /=7.17 Hz, 1 H), 2,85 (s, 3 H), 1.69 (s, 6 H). LCMS: retention time: 1.277 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters- Simfire, 5u, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 liM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 410 (MH⁺).

3-(3-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)pyridin-4-yl)-N- (2-phenylpropan-2-yl)benzamide. To a mixture containing 3-(3- (methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (0.20 g, 0.50 mmol), potassium carbonate (0.30 g, 2,0 mmol) and DMF (1.6 mL) was added (2- bromoethoxy)(tert-butyl)dimethylsilane (0.10 mL, 0.50 mmol) in a steady stream via syringe. The mixture was stirred at 80° C for 4 h, cooled to room temperature, filtered, concentrated and purified on silica gel (0-10% methanol/dichloromethane, 60 min gradient) to afford 3-(3-(N-(2-(tert- butyldimethylsilyloxy)ethyl)methylsulfonamido) pyrldin-4-yl)-N-(2-ρhenylpropan-2- yl)benzamide as a brown oil IH NMR (500 MHz, DMSO-D6) 5 ppm 8.75 (s, 1 H)₅ 8.64 (d, J-4.88 Hz, 1 H), 8.35 (s, 1 H), 7.96 (s, 1 H), 7.91 (d, J-7.94 Hz, 1 H), 7.77 (d, /=7.93 Hz, 1 H), 7.52 - 7.60 (m, 2 H), 7.40 (d, J=I, 32 Hz, 2 H), 7.28 (t, J=7.63 Hz, 2 H), 7.17 (t, J=7.32 Hz, 1 H), 3.42 - 3.50 (m, 1 H), 3.25 (s, 3 H), 3.03 (s, 1 H), 1.64 - 1.71 (m, 6 H)₅ 0.71 - 0.78 (m, 9 H), -0.12 - -0.06 (m, 6 H). LCMS: retention time: 2.497 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6 x 50 mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/rnin, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 568 (MH⁺).

Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyI)methyIsuϊfonamido)-5-(3-(2- phenyIpropan-2-yIcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylate. To a cooled solution (0° C, ice bath) containing 3-(3-(N-(2-(tert- butyldimethylsilyloxy)ethyl)methylsulfonamido)pyridin-4-yl)-N-(2-phenylproρan-2- yl)benzamide (0.090 g, 0.12 mmol) and dichloromethane (2 mL) was added O- (mesitylsulfonyl)hydroxylamine (0.080 g, 0.37 mmol) in dichloromethane (2 mL) quickly, dropwise. The solution was maintained at 0° C for 15 min, removed from the cooling bath and maintained at ambient temperature for 2 h. The solution was concentrated, dissolved in methanol (5 mL) and re-concentrated to afford l-amino-3- (N-(2-hydroxyethyl)rϊiethylsulfonamido)-4-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl) pyridinium 2,4,6 -trimethylbenzenesulfonate as a light yellow foam (470, MH⁺). The product thus obtained was dissolved in DMF (2,4 mL) and added slowly dropwise over 20 min to a cooled mixture (0⁰C, ice bath) containing potassium carbonate (0.070 g, 0.50 mmol), methyl 3-(4-fluorophenyl)propiolate (0.030 g, 0.19 mmol) and DMF (2.0 mL). The mixture was kept in the cooling bath with stirring and allowed to proceed for 15 h at ambient temperature. The mixture was filtered and concentrated. Purification on silica gel (0-100% ethyl acetate/hexanes, 60 min gradient) afforded methyl 2-(4-fluorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl) pyrazolo[lj5-a]pyridme-3-carboxylate as a yellow residue. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 8.72 (s, 1 H), 8.24 (s, 1 H), 8.16 (s, 1 H), 7.97 - 8.00 (m, 1 H), 7.89 (t, J-7.93 Hz, 1 H), 7,77 - 7.84 (m, 2 H), 7.50 - 7.59 (m, 2 H)₅ 7.40 - 7.49 (m, 3 H), 7.23 - 7.33 (m, 3 H)₉ 7.12 - 7.19 (m, 3 H), 3.83 (s, 3 H), 3.62 - 3.71 (m, 1 H), 3.39 - 3.46 (m, 1 H), 3.30 - 3.39 (m, 1 H), 3.18 - 3.23 (m, 3 H), 2.63 - 2.72 (m, 1 H), 1.78 (t, J=I 2.21 Hz, 6 H). LCMS: retention time: 2.403 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters- Sunfϊre, 5u, C 18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 645 (MH⁺).

2-(4-fluorophenyI)~6-(N-(2-hydroxyethyl)methyIsuIfonamido)-5-(3-(2- phenyϊpropan-I-ylcarbamoyOpheny^pyrazolo^S-alpyridine-S-carboxylic acid. To a solution containing methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl) methylsulfonamido)-5-(3-(2-phenylρropan-2-ylcarbamoyl)plienyl)pyrazolo[l,5- a]pyridine-3-carboxylate (0.021 g, 0.33 rntnol), THF (0.20 mL) and methanol (0.13 mL) was added aqueous lithium hydroxide (0.08ImL, 2.0 M). The solution was maintained at room temperature for 20 h, then at 45° C for 8 h. The solution was adjusted to below pH 4 with aqueous HCl (0.21 mL, 1 ,0 N) and extracted with ethyl acetate (2 x 0.50 mL). The combined organic portions were washed with brine (0.50 mL) and concentrated to afford 2-(4-fluorophenyl)-6-(N~(2~ hydroxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid as a light yellow residue which was used without further purification. LCMS: retention time: 1.778 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, CIS, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 631(MH⁺).

2-(4-fluorophenyI)-6-(N-(2-hydroxyethyl)methylsulfonamido)~N-methyl-S-(3-(2- phenylpropan-2-ylcarb amoyl)p heny l)py r azolo [ 1 ,5-a] py rid ine-3-carboxamide. To a solution containing 2-(4-fluorophenyl)-6-(N-(2- hydioxyethyl)methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.021 g, 0.033 mmol), HOAT (0.0050 g, 0.036 mmol), diisopropylethylamine (0.070 mL, 0.40 mmol), methylamine hydrochloride (0.0090 g, 0.13 mmol), dichloromethane (0.70 mL) and DMF (0.14 mL) was added EDCI (0.020 g, 0.10 mmol). The solution was maintained at room temperature for 15 h and concentrated. Purification by preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1 M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 12 min. gradient) afforded 2-(4-iluorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-N-methyl- 5 -(3-(2-phenylpropan~2- ylcarbamoyl)phenyl)pyrazolo[l,5-a]ρyridine-3-carboxamide as a white solid. Preparative HPLC retention time 7.4 min. IH NMR (400 MHz, DMSO-D6) δ ppm 9.13 (s, 1 H), 8.28 (s, 1 H), 8.05 (s, 1 H), 8.00 (q, /=4.27 Hz, 1 H), 7.86 - 7.94 (m, 3 H), 7.78 (d, J=8.03 Hz, 1 H), 7.75 (s, 1 H), 7.56 (t, /=7.78 Hz, 1 H), 7.37 - 7.42 (m, 2 H), 7.25 - 7.35 (m, 4 H), 7.16 (t, /=7.28 Hz, 1 H), 4.95 (t, /=4.89 Hz, 1 H), 3.58 (dd, /=14.18, 5.65 Hz₅ 1 H), 3.38 (s, 2 H), 3.21 - 3.26 (m, 3 H), 2.86 - 2.96 (m, 1 H), 2.75 (d, J=4.52 Hz, 3 H), 1.67 (s, 6 H). LCMS: retention time: 2,825 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 mm, and an analysis time of 5 min where solvent A was 10% methanol / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 644 (MH⁺).

Methyl 2-(4-fl uoroph en yl)~5-methoxy py r azolo [ 1,5-a] py ridine-3-carboxylate.

Methyl 2-(4-fluorophenyl)-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylate was prepared from 4-methoxypyridine (0.55 g, 3.1 mmol). 1 H NMR (500 MHz,

CHLOROFORM-D) δ ppm 8.38 (d, J=7.63 Hz₅ 1 H), 7.73 - 7.77 (m, 1 H), 7,73 (d, /=5.49 Hz, 1 H), 7.49 (d, /=2.75 Hz, 1 H), 7.13 (t, /=8.70 Hz, 2 H), 6.66 (dd, /=7.63, 2.75 Hz, 1 H), 3.94 (s, 3 H), 3.81 (s, 3 H). LCMS: retention time: 2.706 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C 18, 4.6 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 301(MH⁺).

2-(4-fluorophenyi)~5-methoxypyrazolo[l,5-a]pyridine-3-carboxy!k acid. 7, 2-(4- fluorophenyl)-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylic acid was prepared from methyl 2-(4-fluorophenyl)-5-methoxyρyrazolo[ 1 ,5-a]pyridine-3-carboxylate (0.99 g, 3.3 mmol). IH NMR (500 MHz, DMSO-D6) δ ppm 12.30 (s, 1 H), 8.70 (d, /-7.32 Hz, 1 H), 7.79 (dd, /-8.85, 5.80 Hz, 2 H), 7.43 (d, /=2.75 Hz, 1 H), 7.27 (t, J=9.00 Hz, 2 H), 6.83 (dd, /=7.63, 2.75 Hz₅ 1 H)₅ 3.92 (s, 3 H). LCMS: retention time: 1.420 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenoraenex-Luna, 1Ou, C18, 4.6 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 287(MH⁺).

2-(4-fluorophenyI)-5-methoxy-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide. 2-(4-fluorophenyl)-5 -methoxy-N-methylpyrazolo[ 1 ,5 -a]pyridine-3 -carboxamide was prepared from 2-(4-fluorophenyl)-5-methoxypyrazolo[ 1 ,5-a]pyridine-3-carboxylic acid. (0.88 g, 2.6 mmol). IH NMR (500 MHz, MeOD) δ ppm 8.42 (d, J=7.63 Hz, 1 H), 7.71 - 7.78 (m, 2 H), 7.30 (d, J-2.75 Hz_f 1 H)₇ 7.25 (t, J=8.85 Hz, 2 H), 6.73 (dd, J=7.63, 2.75 Hz, 1 H), 3.96 (s, 3 H), 2.86 (s, 3 H). LCMS: retention time: 1.935 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 300(MH⁺).

2-(4-fluorophenyI)-5-hydroxy-N-methylpyrazolo[l,S-a]pyridine-3-carboxamide.

To a suspension containing 2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[l,5- a]pyridine-3-carboxamide (0.30 g, 1.0 mmol) and toluene (10 mL), was added boron tribromide-methylsulfide complex (1.3 g, 4.0 mmol) in one portion. The mixture was stirred in a closed vessel at 105° C for 40 h under a nitrogen atmosphere, cooled to room temperature and extracted with aqueous sodium hydroxide (3 x 20 mL, 2.0 M). The combined aqueous extracts were neutralized with aqueous HCl (2.0 M, approx. 60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic portions were dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5- hydroxy-N-methylpyrazolo[l ,5-a]pyridine-3-carboxamide as a tan solid which was used without further purification. IH NMR (500 MHz, DMSO-D6) δ ppm 10.69 (s, 1 H), 8.55 (d, J=7.32 Hz, 1 H), 7.75 - 7.82 (m, 2 H), 7.50 (d, J=4.58 Hz, 1 H), 7.28 (t, J=9.00 Hz, 2 H), 7.05 (d, J=2.44 Hz, 1 H), 6.65 (dd, 7=7.48, 2.59 Hz, 1 H), 2.72 (d, /=4.58 Hz, 3 H). LCMS: retention time: 1.102 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 285 (MH¹).

2-(4-fluoroph enyl)-3-(methylcarbamoyl)py razol o [ 1 ,5-a] py ridin-5-yl trifluoromethanesulfonate. A solution containing 2-(4-fluorophenyl)-5-hydroxy-N- methylpyrazolo[l_f5-a]pyridine-3-carboxamide (0.25 g, 0.66 mmol), N- Phenylbis(trifluoromethane)sulfonamide (0.35 g, 0.99 mmol), triethylamine (0.46 niL, 3.3 mmol) and dicliloromethane (6.5 mL) was maintained at room temperature for 18 h. The solution was further diluted with dichloromethane (10 mL), washed with saturated, aqueous sodium bicarbonate (10 mL), washed with water (5 mL), dried over MgSO4, filtered and concentrated. Purification on silica gel (0-100% ethyl acetate/hexanes, 45 min gradient) afforded 2-(4-fluorophenyl)-3- (methylcarbamoyl)pyrazolo[ 1 ,5 -a]pyridin-5 -yl trifluoromethanesulfonate as a white solid. IH NMR (500 MHz₅ DMSO-D6) δ ppm 9.00 (d, /=7.63 Hz, 1 H), 7.98 (d, J=2.44 Hz, 1 H), 7.94 (d, J=4.58 Hz, 1 H), 7.83 - 7.89 (m, 2 H), 7.41 (s, 1 H), 7.32 - 7.38 (m, 2 H)₅ 7.25 (dd, J=7.48, 2.90 Hz, 1 H), 2.77 (d, J=4.58 Hz, 3 H). LCMS: retention time: 2.623 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1 Ou, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 418 (MH⁺).

3-(2-(4-fluorophenyi)-3-(methylcarbaraoyl)pyrazoIo[l,5-a]pyridin-5-yl)benzoic acid. To a degassed solution containing 2-(4-fluorophenyl)-3~ (methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl trifluoromethanesulfonate (0,19 g, 0.44 mmol), 3-boronobenzoic acid (0.11 g, 0.67 mmol), cesium carbonate (0.22 g, 0.67 mmol), dioxane (3.7 mL) and water (0.74 mL) was added tetrakis(tiphenylphosphine)paUadium(0) (0.0090 g, 0.010 mmol). The solution was maintained at 95°C for 7 h. The solution was cooled to room temperature, concentrated and dissolved in a solution containing water and methanol (1.8/1, 14 mL). The solution was filtered to remove fine particulates and washed with dichloromethane (3 x 5mL). The aqueous portion was concentrated to dryness to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[ 1 ,5-a]pyridin-5- yl)benzoic acid as a pale grey solid which was used without further purification. LCMS: retention time: 1.830 rain. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C 18, 3,0 x 50 mm column using a SPD-10AV UV~Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 390 (MH⁺).

2-(4-fluorophenyI)-N-methyl-5-(3-(2~phenylpropan-2~ylcarbamoyl)phenyϊ) pyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing 2-phenylpropan- 2-amine (0.040 g. 0.29 mmol), diisopropylethylamine (0,10 mL, 0.58 mmol), 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (0,10 g, 0.20 mmol) and DMF (1 ,3 mL) was added HATU (0.10 g, 0.25 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 12 min. gradient) afforded 2-(4- fluorophenyl)- N -methyl- 5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl) pyrazolo[l,5- ajpyridine- 3-carboxamide as a white solid. Preparative HPLC: retention time: 8.0 min. IH NMR (500 MHz, DMSO-D6) δ ppm 8.90 (d, J=7.32 Hz, 1 H), 8.65 (s, 1 H), 8.26 (s, 1 H), 8.10 (s, 1 H), 8.00 (d, /=6.10 Hz, 2 H), 7.88 - 7.94 (m, 3 H), 7.61 - 7.66 (m, 1 H), 7.49 (dd, 7=7.17, 1.68 Hz, 1 H), 7.42 (d, J=7.63 Hz, 2 H), 7.28 - 7.35 (m, 4 H)₅ 7.19 (s, 1 H), 2.81 (d, J=4.58 Hz, 3 H), 1.72 (s, 6 H). LCMS: retention time: 3.325 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, CIS, 4.6 x 50 mm column using a SPD- 10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 507 (MH⁺).

2-(4-fluorophenyl)-N-methyϊ-5-(3-(l- ph enylcyclopropylcarb amoyl)phenyl)py r azolo [ 1,5-a] pyri dine-3-carbox amide. 2-

(4-fluoroρhenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)pyrazolo [1 ,5 -a]pyridine-3 -carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[ 1 ,5-a]pyridin-5- yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropaiiamine hydrochloride (0.040 g, 0.20 mmol). 1 H NMR (500 MHz, DMSO-D6) δ ppm 9.40 (s, 1 H)₅ 8.90 (d, J=7.32 Hz, 1 H), 8.35 (s, 1 H), 8.11 (d, J=I .22 Hz₅ 1 H), 8.03 (d, J=7.93 Hz₅ 1 H), 7.98 (d, J=7.63 Hz, 2 H), 7.90 (dd, J=8.70, 5.65 Hz, 2 H), 7.65 (t, J-7.78 Hz₅ 1 H), 7.49 (dd, J=7.32, 1.83 Hz, 1 H), 7.28 - 7.35 (m, 4 H), 7.23 - 7.26 (m, 2 H), 7.15 - 7.20 (m, 1 H), 2.81 (d, J=4.58 Hz, 3 H), 1.32 (d, /=9.16 Hz, 4 H). LCMS: retention time: 3.053 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromato graph equipped with a Phenomenex-Luna, 1Ou, C18, 4.6 x 50 mm column using a SPD-10AV L¹V-ViS detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 MM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH⁴).

2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenyl cyclobutyϊcarbamoyl)p henyl)py r azolo [l,5"^al py ridi ne-3-carb oxamid e. 2-

(4-fluorophenyl)-N-methyl-5 -(3 -( 1 -phenylcyclobutylcarbamoyOpheny^pyrazolo [1,5- a]pyridine-3~carboxamide was prepared from 3-(2-(4-fiuoroρhenyl)-3- (methylcarbamoyi)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclobutanamine hydrochloride (0.040 g, 0.20 mmol). IH NMR (500 MHz, DMSO-D6) δ ppm 9.21 (s, 1 H), 8.90 (d, /=7.02 Hz, 1 H), 8.30 (s, 1 H), 8.09 (s, 1 H)₁ 7.96 - 8.03 (m, 2 H), 7.88 - 7.96 (m, 3 H), 7.63 (t, /=7.63 Hz, 1 H), 7.53 (d, /=7.63 Hz₅ 2 H), 7.48 (dd, /=7.32, 1.83 Hz, 1 H), 7.30 - 7.37 (m, 4 H)₅ 7.21 (t, /=7.32 Hz, 1 H), 2.82 (d_> /=4.58 Hz₃ 3 H)₅ 2.63 - 2.71 (m, 2 H), 2.58 (ddd, /=12.13, 8.62, 6.10 Hz, 2 H), 2.03 - 2.11 (m, 1 H), 1.84 - 1.93 (m, 1 H). LCMS: retention time: 3.225 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C18, 4.6 x 30 mm column using a SPD- 10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 519 (MH⁺).

5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5- a]pyridine-3-carboxamide. 5-(3-(tert-butylcarbamoyI)phenyl)-2-(4-fluorophenyl)~ N-methylpyrazolo[l,5-a]pyridme-3-carboxamide was prepared from 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl) pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (0.10 g, 0.20 mmol) and 2-methylpropan-2-amine (0.020 g, 0.30 mmol). IH NMR (500 MHz, DMSO-D6) δ ppm 8.88 (d, J=7.02 Hz₅ 1 H), 8.19 (s, 1 H), 8.09 (d, J=I.22 Hz, 1 H), 7.95 - 8.02 (m, 3 H), 7.87 - 7.93 (m, 3 H), 7.58 - 7.64 (m, 1 H), 7.47 (dd, J=7.32, 1.83 Hz₅ 1 H), 7.33 (t, /-9.00 Hz, 2 H), 2.82 (d, /-4.58 Hz_} 3 H), 1.43 (s, 9 H). LCMS: retention time: 2.940 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 1Ou, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 445 (MH⁺).

4-(benzyloxy)pyricHn»3»amine. To a mixture containing 4-(benzyloxy)-3- nitropyridine (7,2 g, 31.3 mmol) and zinc powder (6.1 g, 91.0 mmol) was added acetic acid (7.2 mL, 7.5 mmol), The mixture was stirred for 6h at room temperature, filtered and concentrated. The resultant residue was dissolved in ethyl acetate (300 mL), washed with aqueous, saturated ammonium chloride (3 x 100 mL), washed with brine (100 mL), dried over MgSO₄, filtered and concentrated to afford A- (benzyloxy)pyridm-3 -amine as an orange oil which was used without further purification. IH NMR (500 MHz, DMSO-D6) δ ppm 7.91 (s₍ 1 H), 7.72 (d, /=5.49 Hz, 1 H), 7.50 (d, /=7.63 Hz, 2 H), 7.41 (t, /=7.32 Hz, 2 H), 7.34 (s, 1 H), 7.03 (d, /-5.49 Hz, 1 H), 5.24 (s, 2 H), 5.13 (s, 2 H). LCMS: retention time: 1.372 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 201 (MH⁺).

N~(4-(benzyIoxy)pyridin-3-yl)methanesulfonamide. To a solution containing A- (benzyloxy)pyridin-3 -amine (6.2 g, 15.8 mmol), triethylamine (11 mL, 79 mmol), and. dichloromethane (163 mL) was added methanesufonylchloride (1.2 mL, 15.8 mmol) in dichloromethane (100 mL) drop wise over 90 min. The solution was maintained at room temperature for 6h and concentrated to afford N-(4- (benzyloxy)pyridin-3-yl)methanesulfonamide which was used without further purification. LCMS: retention time: 1.305 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Xterra, 5 micron, C 18, 4.6 x 30 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 279 (MH⁺).

N-(4-(benzyloxy)pyridin-3-yl)-N-(2-(tert-butyldimethylsiIyloxy)ethyl) methanesulf on amide. N-(4-(benzyloxy)pyridin-3-yl)-N-(2-(tert- butyldimethylsilyloxy)ethyl) methanesulfonamide was prepared from N-(4- (benzyloxy)pyridin-3-yl)methanesulfonamide (4.6 g, 10.6 mmol). IH NMR (400 MHz, DMSO-D6) 5 ppm 8.40 (d, /=5.77 Hz, 1 H), 8.30 (s, 1 H), 7.45 - 7.51 (m, 2 H), 7.33 - 7.43 (m, 3 H), 7.26 (d, /=5.77 Hz, 1 H), 5.27 (s, 2 H), 3.59 (s, 4 H), 2.94 (s, 3 H), 0.78 (s, 9 H), -0.07 (s, 6 H). LCMS: retention time: 3.221 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate, MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 437 (MH^H).

Methyl 6-(N-(2-(tert-butyIdimethylsilyloxy)ethyl)methylsuIfonamido)-2-(4- fluorophenyl)-5-hydroxypyrazolo[l,5-a]pyridine-3-carboxylate. Methyl 6-(N-(2- (tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl) - 5 - hydroxypyrazolo [l,5-a]pyridine-3-carboxylate was prepared from N-(4- (benzyloxy)pyridin"3~yl)-N-(2~(tert-butyldimethylsilyloxy)eth.yl) methanesulfonamide (2.4 g, 5.5 mmol). IH NMR (500 MHz, CHLOROFORM-D) δ ppm S.50 (s_} 1 H), 7.69 - 7.75 (m, 2 H), 7.66 (s, 1 H), 7.39 - 7.47 (m, 5 H), 7.13 (t, /=8.70 Hz, 2 H), 5.24 (s, 2 H), 3.81 (s, 4 H), 3.74 (s, 3 H), 2.87 (s, 3 H), 0.80 (s, 9 H), -0,01 (s, 6 H). LCMS: retention time: 3.190 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, C 18, 4.6 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 254 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 628 (MH⁺).

Methyl 2-(4-flu orophenyI)-5-hydroxy-6-(N-(2-hy droxy ethyl) methylsulfonamido) pyrazolo[l,5-a]pyridine-3-carboxylate. To a solution containing Methyl 6-(N-(2-(tert-butyldimethylsilyloxy)ethyl) methylsulfonamido)-2- (4-fluoroρhenyl)-5-hydroxypyrazolo [l,5-a]pyridine~3-carboxylate (0.17 g, 0.27 mmol) and ethyl acetate (5.4 mL) was added 10% Pd/C (0.04 g, 0.04 mmol Pd) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford Methyl 2-(4-fluorophenyl)-5-hydroxy-6-(N-(2»hydroxyethyl) methylsulfonamido)pyrazolo[l,5-a]pyridine-3-carboxylate as a light yellow oil. IH NMR (400 MHz, DMSO-D6) δ ppm 11 -71 (s, 1 H), 8.68 (s, 1 H), 7.73 (ddd, J=I 1.98, 5.33, 2.76 Hz, 2 H), 7.46 (s, 1 H), 7.25 - 7.31 (m, 2 H), 3.70 (s, 7 H), 3.11 - 3.14 (m, 3 H), 0.74 (s, 9 H), -0.06 - -0.04 (m, 6 H). LCMS: retention time: 2.750 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, C 18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM, The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 raM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 538 (MH⁺).

Methyl 6-{N~(2-(tert~butyldimethyIsϊlyloxy)ethyI)methyIsulfonamido)-2-(4- fluorophenyl)-5-(trifluoromethylsulfonyloxy)pyrazolo[l,5-a]pyridine-3- carboxylate. Methyl 6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)- 2-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)pyrazolo[l,5-a]pyridine-3- carboxylate was prepared from Methyl 2-(4-fluoroplienyl)-5-hydroxy-6-(N-(2- hydroxyethyl) methylsulfonamido) pyrazolo[l,5-a]ρyridine-3 -carboxylate (0.15 g, 0.29 mmol). LCMS: retention time: 3.200 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of

100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 670 (MH⁺).

3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyI)methylsulfonamido)-3- (methoxycarbonyI)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid. 3-(2-(4- fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3- (methoxycarbonyl)pyrazolo[l,5~a]pyridin-5-yl)benzoic acid was prepared from Methyl 6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4- fluorophenyl)-5-(trifluoromethyl- sulfonyloxy)pyrazolo[ 1 ,5-a]pyridine-3-carboxylate (0.07 g, 0.10 mmol). LCMS: retention time: 1.845 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, CIS, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 528 (MH⁺).

Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonaraido)-5-(3-(l- (pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3- carboxylate. Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)- 5-(3-(l-(pvridin-2-yl)cyclopropylcarbamoyl) phenyl)pyrazolo[l,5-a]pyridine~3- carboxylate was prepared from 3-(2-(4-fluorophenyl)-6-(N-(2~ hydroxyethyl)methylsulfonamido)~3-(methoxycarbonyl)pyrazolo[l,5-a]pyridin-5- yl)benzoic acid (0,05 g, 0.10 mmol) and l-(pyridin-2-yl)cyclopropanamine dihydrocMoride (0.03 g, 0.15 mmol). LCMS: retention time: 1.473 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 254 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 644 (MH⁺).

2-(4-fluorophenyI)-6-(N-(2-hydroxyethyl)methylsuIfonamido)-5-(3-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a)pyridiiie-3-carboxylic acid. 2- (4~fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonatnido)-5-(3-(l-(pyridin-2- y^cyclopropylcarbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid was prepared from methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)- 5-(3-(l-(ρyridin-2-yl)cycloρropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3- carboxylate (0.06 g, 0.10 mmol). LCMS: retention time: 1.220 min. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a Waters- Sunfire, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient lime of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 630 (MH⁺).

2-(4-fluorophenyl)-6-(N-(2-hydroxyethyI)methylsulfonamido)-N~π»ethyl~5-(3-(l- (pyridin-2-yI)cyclopropylcarbamoyl)phenyl)pyrazoIo(l,5-a]pyridine-3- carboxamide. 2-(4-fluoroρhenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N- methyl-5-(3-(l-(pyridm-2-yl)cyclopropyl carbamoyl)phenyl)pyrazolo[l,5-a]pyridine- 3-carboxamide was prepared from 2-(4-fluorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-5-(3-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.04 g, 0.06 mmol). IH NMR (500 MHz, DMS0-D6) δppm 9.26 (s, 1 H), 9.16 (s, 1 H), 8.45 (d, /-3.05 Hz, 1 H), 8.11 (s, 1 H), 8.05 (q, J-4.27 Hz, 1 H), 7.95 - 8.01 (m, 1 H), 7.88 - 7.93 (m, 2 H), 7.87 (d, J=8.24 Hz, 1 H), 7.78 (s, 1 H), 7.65 - 7.70 (m, 1 H), 7.59 - 7.64 (m, 1 H), 7.31 - 7.40 (m, 3 H), 7.16 (dd, J=7.02, 5.19 Hz, 1 H), 5.01 (s, 1 H)_f 3.58 - 3.65 (m, 1 H), 3.42 (s, 1 H), 3.25 (s, 4 H), 2.94 (dt, J-14.65, 4.43 Hz, 1 H), 2.74 - 2.78 (m, 3 H), 1.53 - 1.59 (m, 2 H), 1.24 - 1.31 (m, 2 H). LCMS: retention time: 1.517 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 mm, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% H₂O M 0 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 643(MH⁺).

Ethyl 6-bromo-2-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxylate. Ethyl 3- (4-fiuorophenyl)-3-oxopropanoate (2.6 g, 12 mmol) was dissolved into DCM (32 mL), cooled to 0 ⁰C and treated with tetra-n-butylammonium tribromide (6.75 g, 14.0 mmol). The reaction mixture was stirred at 0 ⁰C for Ih, rt for Ih and then washed with sat NaHCO₃ (aq) (2 x 50 mL)₅ dried (MgSO₄), filtered and concentrated. The crude material was dissolved into EtOH (60 mL) and then 5-bromopyridin-2-amine (6.22 g, 36.0 mmol) was added and the reaction was stirred at 70 ⁰C under nitrogen overnight (complete by LCMS). The reaction mixture was diluted with DCM (-120 mL), washed with sat. NaHCO₃ (aq) (2 x 100 mL) and the organic layer was dried (MgSO4), filtered and concentrated. The resulting solid was dissolved into DCM (-30 inL), diluted with hexanes (-70 niL) and stirred. The solids were filtered away (contained some desired product) and the mother liquor was concentrated, dissolved into DCM and purified by Biotage Horizon (4OM, 10% EtO Ac/hex, SiO₂) (the compound crashed out in the instrument resulting in an unknown quantity being shunted to waste). The collected fractions had solid material precipitating out which was collected by filtration to yield ethyl 6-bromo-2-(4-fluorophenyl)imidazo[l,2- a]pyridine-3-carboxylate (594 mg, 1.636 mmol, 13% yield) as a white fluffy solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.60 (s, IH), 7.75 (d, J = 8.4 Hz, IH), 7.74 (d, J = 8.4 Hz, IH), 7.62 (d, J = 9.2 Hz, IH), 7.52 (dd, J = 9.2, 1.5 Hz, IH), 7.13 (d, J- 8.5 Hz, IH), 7.12 (d, J = 8.5 Hz, IH), 4.33 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). LCMS : m/e = 743 (M+H)⁺, retention time = 2.24 min, (Column = (2)phenomenex 4.6x50mmC18 lOum, Solvent A = 10% MeOH - 90% H₂O - 0.1% TFA, Solvent B = 90% MeOH - 10% H₂O - 0.1% TFA Start % B - O, Final % B = 100, Gradient Time = 2 min, Hold time = 1 min, Flow Rate = 5 mL /min). LC- MS retention time 2.04 min; m/z 362, 364 (MH+). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

6-Bromo-2-(4-fluorophenyl)imidazo[l,2-a]pyddine»3-carboxylic acid. Ethyl 6- bromo-2-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxylate (394 mg, 1.09 mmol) was dissolved into MeOH (10 mL) and THF (10 mL) and then IM aqueous NaOH (7.5 mL, 7.50 mmol) was added and the reaction was heated at 70 ⁰C for Ih, The reaction was treated with aqueous IM HCl (8 mL) (white prec. formed), cooled to rt, diluted with water (30 ml) and filtered to collect the precipitate (rinsed with water). The solid was dried overnight under vacuum to yield 6-bromo-2-(4- fluorophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (290 mg, 0.87 mrnol, 80% yield) as a white solid. ¹H NMR (500 MHz, DMSOd₆) δ ppm 13.40 (br s, IH), 9.53 (s, IH), 7.86 (d, J = 8.6 Hz, IH), 7.84 (d, / = 8.6 Hz, IH), 7.78 (d, J = 9.5 Hz, IH), 7.73 (dd, J = 9.5, 1.5 Hz, IH)₅ 7.30 (d, J = 8.9 Hz, IH), 7.28 (d, J= 8.9 Hz, IH). LC-MS retention time 0.94min; m/z 334, 336 (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C 18 4.6x50mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 10% H2O / 90% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

6-Bromo-2-(4-fluorophenyl)-N-methylimidazo [l,2-a]pyridine-3-carboxamide. 6-

Bromo-2-(4-fluorophenyl)imidazo[l,2-a]pyridine-3-carboxylic acid (250 mg, 0.746 mmol) was slurried into DCE (8 mL) and then oxalyl chloride (0.30 mL, 3.4 mmol) was added and the slurry was stirred for 5 min. Then DMF (50 μL, 0.65 mmol) was added (foaming) and the slurry was stirred Ih before methanarnine (5 mL, 10 mmol) 2M in THF (exothermic) and TEA (~3 mL) (exothermic) were added. The reaction was stirred at rt overnight. The reaction was partitioned between water (-30 mL) and DCM/MeOH (9/1, 3 x 30 mL). The combined organics were concentrated to dryness and the residue was slurried in MeOH/EtOAc (1 :1 ~40 mL) and filtered to collect 6- bromo-2-(4-fluorophenyl)-N-methylimidazo[l,2-a]pyridine-3-carboxamide (172 mg, 0.494 mmol, 66% yield) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.92 (s, IH), 8.25 (s, IH), 7.85 (d, J = 7.9 Hz, IH), 7.83 (d, J - 7.9 Hz, IH), 7.69 (d, J = 9.5 Hz, IH), 7.56 (d, J = 9.5 Hz, IH), 7.33 (d, J = 8.5 Hz, IH), 7.31 (d, J- 8.5 Hz₃ IH), 2.79 (d, J = 4.0 Hz, 3H). LC-MS retention time 1.73 min; m/z 348, 350 (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1 Ou Cl 8 4,6x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 niL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

3~(2~(4~FluorophenyI)-3~(methylcarbamoyl)imidazo[l,2-a]pyridin-6-yl)benzoic acid. 6-Bromo-2-(4-fluoroρhenyl)-N-methylimidazo[l,2-a]pyridine-3-carboxamide (150 mgj 0.431 mmol) and 3-boronobenzoic acid (107 mg, 0.646 mmol) were slurried into dioxane (5 mL) and water (1 mL). To the reaction mixture was added Cs₂CO₃ (211 mg, 0.646 mmol) followed by Pd(PPh₃)₄ (50 mg, 0.043 mmol). The reaction was sealed and heated at 100 ⁰C overnight. The reaction solution was cooled to rt, filter to remove solids, diluted with water (~10 mL) and acidified with IN HCl (aq) (1.5 mL, 1.5 mmmol). The white precipitate that formed was collected by filtration, washed with water and dried to yield 3-(2-(4-fluorophenyl)-3- (methylcarbamoyl)imidazo [ 1 ,2-a]pyridin-6-yl)benzoic acid ( 174 mg, 0.335 mmol, 78% yield) as a white solid. ¹H NMR (500 MHz₅ DMSOd₆) δ ppm 13.15 (br s. 1 H), 9.01 (s, IH), 8.25 - 8.17 (m, 2H), 8.00 (t, J = 7.5 Hz, 2H), 7.87 (d, J = 8.7 Hz, IH), 7.86 (d, J = 8.6 Hz, IH), 7.67 (t, J = 7.8 Hz, IH), 7.65 - 7.59 (m, IH), 7.59 - 7.53 (m, IH), 7.32 (d, J - 8.9 Hz, 2H), 2.82 (d, J = 4.0 Hz, 3H). LC-MS retention time 1.18min; m/z 388 (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 4, 6x5 Omm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 mrn, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

6-(3-(tert-Butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylimidazo[l,2- a]pyridine-3-carboxamide. 3-(2-(4-Fuorophenyl)-3- (methylcarbamoyl)irnidazo[l,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) was slurried into DMF (0.7 mL) and TEA (0.1 mL). To this slurry was added 2- methylpropan-2-amine (11.27 mg, 0.154 mmol) and then HATTJ (59 mg, 0.15 mmol) (solution became yellow). The reaction was stirred at rt overnight (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/ water, with 10 mM ammoniun acetate buffer) to yield 6-(3-(tert- butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylimidazo[ 1 ,2~a]pyridine-3- carboxamide (19.6 mg, 0.042 mmol, 41% yield) as a white solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.25 (br s, IH), 8.08 (t, / = 1.8 Hz, IH), 7.90 (dd, J = 9.2, 1.8 Hz, IH), 7.88 - 7.85 (m, IH), 7.84 - 7.82 (m, IH), 7.81 - 7.78 (m, 2H), 7.77 (br d, J = 9.2 Hz, IHX 7.61 (t, J = 7.8 Hz, IH), 7.29 (t, J = 8.9 Hz, 2H), 2.69 (s, 3H)₅ 1.52 (s, 9H). LC-MS retention time 1.39 min; m/z 443 (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 4.6x50rom column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

2-(4-FIuorophenyl)-N-methyI-6-(3-(2-phenyIpropan-2- ylcarbamoyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. 3-(2-(4- Fluorophenyl)-3-(rnethylcarbamoyl)imidazo[l ,2-a]pyridin-6-yl)benzoic acid (40 mg, 0,10 mmol) and 2-phenylpropan-2-amine (21 mg, 0.15 mmol) were dissolved into DMF (0.7 roL) and TEA (0.1 mL). HATU (59 mg, 0.15 mmol) was added to this solution (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0,7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammoniun acetate buffer) to yield 2-(4- fluorophenyl)-N-methyl-6-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)imidazo-[ 1 ,2- a]pyridine-3-carboxamide (24,1 mg, 0.045 mmol, 44% yield) as a white solid. ¹H NMR (500 MHz, CD₃OD) δ ppm 9.25 (br s, IH), 8.14 (br s, IH), 7.92 - 7.86 (m 3H), 7.81 - 7.79 (m, 3H), 7.63 (t, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.6 Hz₅ 2H), 7.35 (d, J = 7.3 Hz, IH)₅ 7.33 (d, J = 8.2 Hz, IH), 7.29 (d, J = 8.9 Hz, IH), 7.27 (d, J = 8.6 Hz, IH), 7.22 (t, J = 7.2 Hz, IH), 2.90 (s, 3H), 1.81 (s, 6H). LC-MS retention time 1.74 min; m/z 507 (MH+). LC data was recorded on a Sbimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min_s and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 10% H2O / 90% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

2-(4-Fluorophenyl)-N-methyl-6-(3-(l~ phenylcyclopropylcarbamoyI)phenyl)imidazo[l,2-a]pyridine-3-carboxamide. 3-

(2-(4-Fluoroρhenyl)-3-(niethylcarbamoyl)imidazo[l,2~a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) and l-phenylcyclopropaiiamine, HCl (26 mg, 0.15 mmol) were slurried into DMF (0.7 mL) and TEA (0.1 mL), HATU (59 mg, 0.15 mmol) was added to this slurry (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammom^'un acetate buffer) to yield 2-(4-fluorophenyl)-N-methyl-6-(3 -( 1 - phenylcycloproρylcarbamoyl)phenyl)imidazo[l,2-a]pyridine-3-carboxamide (15.2 mg, 0.028 mmol, 28% yield) as a white solid. ¹H NMR (500 MHz, CD₃OD) δppm 9.27 (br s, IH), 8.31 (br s, IH), 7.97 - 7.88 (m 3H), 7.82 - 7.76 (m, 3H), 7.66 (t, J = 7.8 Hz, IH), 7.35 - 7.26 (m, 6H), 7.22 - 7.17 (m, IH), 2.90 (s, 3H), 1.45 - 1.36 (m, 4H). LC-MS retention time 1.63 rnin; m/z 505 (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 10% H2O / 90% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

11297 PCX

Ethyl 2-(5-bromo-2-nitrophenyl)-3-(4-fluorophenyl)-3-hydroxyacrylate.

Potassium carbonate (3.3 g, 24 mmol) was added to a stirred solution of 4-bromo-2- fluoro- 1 -nitrobenzene (2.45 g, 11 mmol) and ethyl 3-(4-fluorophenyl)-3- oxopropanoate (2.7 g, 13 mmol) in DMSO (11 mL). The yellow solution turned purple and the reaction was stirred at r.t. After 8 h_s the reaction was neutralized with 25 mL of 1 N HCl and extracted with EtOAc. The organic phase was washed with water (x3) and brine, dried over Na₂SO^ filtered, and concentrated. The residue was purified by silica gel chromatography on a Biotage 40+M column (gradient elution 5% to 25% EtOAc/hexanes over 10 column volumes, fraction collection at λ = 254 nm) to afford the title compound as a viscous amber oil, 4.8 g (105% yield, contains -10 weight % EtOAc by ¹H NMR). ¹H NMR (-0.6:1 ratio of ketoxnol tautomers, 500 MHz, CDCl₃) δ ppm 13.47 (s, 1 H) 7.94 - 8.05 (m, 2 H) 7.86 (d, /= 8.55 Hz, 1 H) 7.62 - 7.72 (m, 1.2 H) 7.51 (dd, J = 8.55, 2.14 Hz, 1 H) 7.29 - 7.35 (m, 2 H) 7.15 - 7.21 (m, 1.2 H) 7.12 (d, J= 2.14 Hz, 1 H) 6.94 (t, J= 8.55 Hz, 2 H) 6.35 (s, 0.6 H) 4.20 - 4.34 (m, 2 H) 4.04 - 4.11 (m, 1.2 H) 1.23 - 1.27 (m, 2 H) 1.18 (t, J= 7.17 Hz, 3 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A = 5% CH₃CN/95% H₂O/10 mM NH₄OAc, solvent B = 95% CH₃CN/5%H₂O/10 mM NH₄OAc, start %B = 0, final %B = 100, gradient time = 2 min, stop time = 3 min, flow rate = 5 ml/min, column: XBridge Cl 8 5 μm 4.6 x 50 mm; 2 peaks elute with HPLC R₁ = 1.69 and 1.83 min (~1 :2 ratio), (ES-) m/z (M^") for both = 408, 410 (1 :1 ratio).

Ethyl 5-bromo-2-(4-fluoropheuyl)-lH-indole-3-carboxyIate. Iron powder (710 mg, 13 mmol) was added to a stirred solution of ethyl 2-(5-bromo-2-nitrophenyl)-3- (4-fluorophenyl)-3-hydroxyacrylate (1.0 g, 2.4 mmol) in EtOH (20 mL)/AcOH (16 mL) in a 250 mL round bottomed flask. The flask was immediated placed in a preheated (100 ⁰C) oil bath under an air condenser and the slurry was stirred vigorously, After 1.5 h, the reaction was cooled to r.t., diluted with EtOAc (200 mL), and the solids were removed by filtration. The filtrate was washed with water repeatedly until the organic phase was no longer red, The organic phase was then washed with sat'd NaHCO₃ and brine, dried over Na₂SO₄, filtered, and concentrated (PhMe azeotrope to remove residual AcOH) to give an off-white solid. The crude product was triturated with 1 : 1 CHaCVhexanes and the filtrate purified by silica gel chromatography with a Biotage 40+M cartridge (gradient elution 10% to 40% EtOAc/hexanes over 10 column volumes, fraction collection at λ = 254 tan), The off-white ppt. from above was further triturated with CH₂CI₂ to give a white solid, and the filtrate was concentrated to give an off-white solid. Both ppt. and filtrate were chromatographed separately with the same method as above, but with fraction collection at λ = 320 nm. Each of the three columns afforded two major peaks. The combined first peaks elute were concentrated to give the title compound (335 mg, 38% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.67 (br. s., 1 H) 8.36 (br. s., 1 H) 7.54 - 7.70 (m, 2 H) 7.36 (d, J= 7.68 Hz, 1 H) 7.25 (t, J= 7.68 Hz, 1 H) 7.11 (t, J= 8.23 Hz, 2 H) 4.31 (q, J= 6.83 Hz, 2 H) 1.33 (t, J= 7.14 Hz, 3 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A = 5% CH₃CN/95% H₂OAO mM NH₄OAc, solvent B = 95% CH₃CN/5%H₂O/10 mM NH₄OAc₅ start %B = 0, final %B = 100, gradient time = 2 min, stop time = 3 min, flow rate = 5 ml/min, column: XBridge Cl 8 5 μm 4.6 x 50 mm; HPLC R_t = 1.73, (ES+) m/z (MH⁺) - 362, 364 (1 : 1 ratio).

5-bromo-2-(4-fluorophenyI)-N-methyHH-indole-3-carboxamide. A suspension of ethyl 5-bromo-2-(4-fluorophenyl)-lH-indole-3-carboxylate (90 mg, 0.25 mmol) in 1,2-dichloroethane (3 mL) was cooled in an ice bath under an atmosphere OfN₂. A solution of boron tribromide in CH2CI2 (1 M, 0.75 mL, 0.75 mmol) was added the reaction was allowed warm to r.t. under N₂ over 4 h. Then the reaction was then quenched by the addition of a solution of methylamine in THF (2 M, 5 mL, 10 mmol). The reaction was partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to give a colorless oil. Et₂θ/hexanes was added and a white precipitate formed. The powder was collected by filtration, washed with Et₂O, and air dried to give the title compound (60 mg, 70% yield). ¹H NMR (500 MHz, DMSO-ds) 6 ppm 11.93 (s, 1 H) 7.82 (d, J= 1,83 Hz, 1 H) 7.71 - 7.78 (m, 3 H) 7.32 - 7.41 (m, 3 H) 7.29 (dd, J= 8.55, 1.83 Hz, 1 H) 2.75 (d, J - 4,58 Hz, 3 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A - 5% CH₃CN/95% H₂O/10 mM NH₄OAc, solvent B = 95% CH₃CN/5%H₂O/10 mM NH₄OAc, start %B = 0, final %B = 100, gradient time = 2 min, stop time = 3 min, flow rate = 5 ml/min, column: XBridge Cl 8 5 μm 4.6 x 50 mm; HPLC R_t = 1.26, (ES+) m/z (MH* ) = 347, 349 (1:1 ratio).

3~(2-(4-fluorophenyl)-3-(methyicarbamoyl)-lH-indoI-5-yl)benzoic acid. In a 7 niL scintillation vial were combined 5-bromo-2-(4-fluorophenyl)-N-methyl- 1 H- indole-3-carboxamide (59 mg, 0.17 mmol), 3-boronobenzoic acid (47 mg, 0.28 mmol), Cs₂CO₃ (100 mg, 0.31 mmol), and Pd(PPh₃)₄ (17 mg, 0.015 mmol). 1,4- Dioxane (1,25 mL) and water (0.25 mL) were added, the vial was capped, and the reaction was heated in an oil bath to 90 ⁰C. After 7 h, the reaction was cooled to r.t. and diluted with water. 1 mL of 1 N HCl was added and a ppt. fonned. The suspension was extracted with EtOAc (+ MeOH to aid dissolution), and the organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a tan solid. This was purified by prep HPLC, and concentrated to give a white solid, (12 mg, 18% yield). ¹H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1 H) 8.06 (s, 1 H) 7.97 (d, J= 7.63 Hz, 1 H) 7.92 (d, J= 7.93 Hz, 1 H) 7.65 - 7.74 (m, 2 H) 7.54 (t, J= 7.78 Hz, 1 H) 7.51 (s, 2 H) 7.23 (t, J- 8.85 Hz, 2 H) 2.89 (s, 3 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A - 5% CH₃CN/95% H₂O/10 mM NH₄OAc₅ solvent B - 95% CH₃CN/5%H₂O/10 mM NH₄OAc, start %B = 0, final %B = 100, gradient time = 2 min, stop time = 3 min, flow rate = 5 ml/min, column: XBridge C18 5 μm 4.6 x 50 mm; HPLC R_t = 0.88, (ES+) m/z (MH⁺) = 389.

2-(4-fluorophenyl)-N-methyl-S-(3-(2-phenylpropan-2"yIcarbamoyl)phenyl)-lH~ indoIe-3-carboxamide. To a solution of 3-(2-(4-fluorophenyl)-3- (methylcarbamoyl)-lH-indol-5-yl)benzoic acid (12 mg, 0.031 mmol) and DIPEA (20 μL, 0.115 mmol) in 1,2-dichloroethane (0.5 mL)/DMF (0.1 mL) was added cumylamine (15 μL, 0.10 mmol) and HATU (15 mg, 0.039 mmol). The reaction was stirred at r.t. for 30 min, then the volatiles were evaporated and the residue was purified directly by prep HPLC. Concentration afforded the title compound as a white powder (11 mg, 68% yield). ¹H NMR (500 MHz, MeOD) δ ppm 8.52 (s, 1 H) 8.09 (d, J= 7.93 Hz, 2 H) 7.85 (d, J= 7.63 Hz, 1 H) 7.66 - 7.77 (m, 3 H) 7.49 - 7.57 (m, 3 H) 7.47 (d, J= 8.24 Hz, 2 H) 7.31 (t, J= 7.78 Hz, 2 H) 7.23 (t, J= 8.85 Hz, 2 H) 7.19 (t, J= 7.32 Hz, 1 H) 2.89 (s, 3 H) 1.78 (s, 6 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 inn and Waters Micromass. LC/MS method: solvent A = 10% CH₃CN/90% H₂O/0.1% TFA, solvent B - 90% CH₃CN/10% H₂O/0.1% TFA, start %B = 0, final %B = 100, gradient time = 3 min, stop time = 4 min, flow rate = 4 ml/min, column: Sunfire Cl 8 5 μm 4.6 x 50 mm; HPLC Rt = 1.49 min, (ES+) m/z (MH⁺) = 506. Analytical HPLC method: solvent A - 5% CH₃CN/95% H₂O/0.1% TFA, solvent B = 95% CH₃CN/5% H₂CVO.1% TFA, start %B = 10, final %B = 100, gradient time = 15 min, stop time = 18 min, flow rate = 1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6 x 150 mm, R_t = 15.29 min, purity = 97%; column: Waters Xbridge Phenyl 3.5 μm 4.6 x 150 mm, R₄ = 11.59 min, purity = 98%.

For the experimental procedures that follow until noted the LCMS conditions employed were: Luna 4.6x50mm SlO, Wavelegnth = 220 rrm, flow rate = 4 mL/niin, gradient = 5 to 95% acetonitrile in 1OmM aqueous ammonium acetate.

Methyl 6-iodo-2-phenyipyrazolo[l,5-a]pyridine-3-carboxyIate. Dichloromethane (10 mL) and 3-ϊodopyridine (928 mg, 4.53 mmol) were charged to a 100 mL round- bottomed flask equiped with a magnetic stir bar. This colorless solution was cooled on an ice bath and 0-(mesitylsulfonyl)hydroxylamine (975 mg, 4.53 mmol) in dichloromethane (10 mL) was added dropwise over 5 minutes. After to stirring at room temperature for 30 minutes, the solvent was removed by rotory evaporation to give a white solid. Methyl phenylpropiolate (1000 mg, 6.24 mmol) was added in dimethyl formamide (9 mL). Potassium carbonate (2504 mg, 18.12 mmol) was added. Reaction slowly turned dark green. After stirring at room temp for 2 hours, the reaction was poured into diethyl ether (300 mL and extracted 8x 25 mL water. The solvent was removed from the organic portion by rotory evaporation. The crude product was dissolved in a minimum amount of dichloromethane and charged to a 9Og "Single Sep" silica gel cartridge and eluted with 0 to 40% ethyl acetate in hexanes over 1000 mL. The title compound (200 mg, 12%) was isolated as an orange solid.. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 3.83 (s, 3 H) 7.46 (m, 3 H) 7.59 (dd, J=9.16, 1.53 Hz, 1 H) 7.75 (m, 2 H) 8.00 (dd, J=9.31, 0.76 Hz, 1 H) 8.82 (s, 1 H). LCMS: 2.4 minutes, M+l = 379.

6-Io do-2-p heny lpy razolo [ 1 ,5-a] pyr id in e-3-carb oxyϊic acid. Methyl~6-iodo-2- phenylρyrazolo[l,5-a]pyridine-3-carboxylate (250 mg, 0.661 mmol) was dissolve in aqueous LiOH(2N,l mL), methanol(2mL) and tetrahydrofuran(7 mL). This solution was stirred overnight at 45°C. After 24 hours, 2 mL 2M LiOH and 2 mL methanol were added. Heated at 55°C overnight. The reaction was cooled on an ice water bath and aqueous hydrochloric acid(10 mL, IN) was added drowise until acidic by pH paper. Ethylacetate (200 mL) and water (40 mL) were added. The organic portion was extracted with brine (20 mL) and was dried over magnesium sulfate. The solvent was removed by rotory evaporation. The residue was place under vacuun overnight to give of a white solid (204 mg, 85%). IH NMR (500 MHz, DMSO-D6) δppm 7.47 (m, 3 H) 7.77 (m, 2 H) 7.97 (d, J-9.46 Hz, 1 H) 9.27 (s, 1 H).

6-Iodo-N-methyl-2-phenylpyrazolo[l,S-a]ρyridine-3-carboxamide. To a 250 mL round-bottomed flask equiped with a magnetic stir bar was charged 6-iodo-2- phenylpyrazolo[l,5-a]pyridine-3-carboxylic acid (200 mg, 0.549 mmol), 1-Hydroxy- 7-azabenzotriazole (74.8 mg, 0.549 mmol), methylamine hydrochloride (55.6 mg, 0.824 mmol), diisopropylethylamine (671 μL, 3.84 mmol), dichloromethane (5000 μL) and dimethylforamide (500 μL). To this yellow solution l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg, 0.769 mmol) was added. The reaction was stirred at room temperature for six hours and diluted with ethylacetate (20OmL). The organic portion was washed 5x with 0.5N hydrochloric acid, Ix saturated sodium bicarbonate and 2x brine. The organic portion was dried over magnesium sulfate. The solvent was removed by rotory evaporation. The residue was place under vacuun overnight to give a white solid (130 mg, 90%). IH NMR (500 MHz, MeOD) δ ppm 2.87 (m, 3 H) 7.51 (m, 3 H)

7.63 (dd, J=9.31, 1.37 Hz, 1 H) 7.76 (m, 3 H) 8.94 (s, 1 H). LCMS: 1.8 minutes, M+l - 378.

6-(2-Meth oxy phenyI)-N-methyl~2-p henylpyr azolo [ 1,5-a] py ridine-3- carboxamide. To a microwave vial equipped with a magnetic stir bar was charged 2-methoxyphenylboronic acid (12.09 mg, 0.080 mmol), 6-iodo-N-methyl-2- phenylpyrazolo[l,5-a]ρyridme-3-carboxamide (15 mg, 0.040 mmol), sodium carbonate (7.38 mg, 0.070 mmol), palladium(II) acetate (0.893 mg, 3.98 μmol) and dimethylforamide (1.0 mL). This mixture was placed under an argon atmosphere and heated at 15O⁰C for 10 minutes. The title compound (5.7 mg, 36%) was isolated by reverse phase HPLC: Start %B = 30 to Final %B= 80, Gradient time = 10 minutes, Flow Rate = 35 mL/minute, Wavelenght = 220 ran, Solvent A = 10% methanol, 90% water with 0.1% TFA; Solvent B = 90% methanol, 10% water with 0.1% TFA, Column = Phenomenex-Luna 30 X 50 mm SlO, Product peak at 7.6 minutes. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 2.85 (d, /=4.88 Hz, 3 H) 3.86 (s, 3 H) 7.03 (d, J=7.93 Hz, 1 H) 7.08 (t, J=7.02 Hz, 1 H) 7.39 (m, 2 H) 7.54 (m, 3 H) 7.63 (dd, J=9.16, 1.53 Hz, 1 H) 7.69 (m, 1 H) 8.36 (dd, /=9.16, 0.61 Hz, 1 H) 8.76 (m, 1 H). LCMS: 2.0 minutes, M+l = 358.

Methyl 2-(4-fluorophenyl)~5-methoxybenzolb]thiophene-3-carboxylate. To a cooled solution (-78^° C, dry ice, acetone) containing 2-(4-fluorophenyl)-3-iodo-5- methoxybenzo[b]thiophene (1.0 g, 2.6 mmol,) and THF (26 mL) was added n- butyllithium (2.0 mL, 1.0 M THF) over 5 min. The solution was maintained at -78^° C for Ih. Methylchloroformate (0.80 mL, 10,4 mmol) was then added quickly in a steady stream via syringe. The solution was removed from cooling and allowed to stand at ambient temperature for 15 h. The solution was concentrated and purified on silica gel (0-10% ethyl acetate/hexanes, 40 min. gradient) to afford methyl 2-(4- fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate as a yellow residue. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 7.88 (d, J-2.44 Hz, 1 H), 7.66 (d,

J=8.85 Hz₅ 1 H), 7.47 (dd, J=8.85_f 5.19 Hz, 2 H), 7.12 (t, J=8.70 Hz, 2 H), 7.05 (dd, J=8.70, 2.59 Hz, 1 H), 3.91 (s, 3 H), 3.74 (s, 3 H). LCMS: retention time: 3.355 min. LC data was recorded on a Shimadzu LC-IOAS liquid chroraatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 niM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 317(MH⁺).

Z-^-fluorophenyO-S-methoxybenzoIblthiophene-S-carboxylic acid. To a solution containing methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate (0.59 g, 1.9 mmol), THF (13.5 mL) and methanol (8.5 mL) was added aqueous lithium hydroxide (9.3 mL, 2.0 M). The solution was maintained at 50° C for 15 h. The solution was cooled to room temperature, adjusted to below pH 4 with aqueous HCl (22 mL, 1.0 N) and extracted with ethyl acetate (3 x 15 mL). The combined organic portions were washed with brine (15 mL), dried over MgSO₄, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid as white solid which was used without further purification. IH NMR (500 MHz, DMSO-D6) δ ppm 12.99 (s, 1 H), 7.93 (d, /=8.55 Hz, 1 H), 7.80 (d, J=IAA Hz, 1 H), 7.59 (dd, /=8.55, 5.49 Hz, 2 H), 7.32 (t, /=8.70 Hz, 2 H), 7.11 (dd, /=8.85, 2.44 Hz, 1 H), 3.82 - 3.87 (m, 3 H). LCMS: retention time: 1.532 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 4.6 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 303(MH⁺).

2-(4-fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3-carboxamide. To a solution containing 2-(4-fluorophenyl)~5-methoxybenzo[b]thiophene-3-carboxylic acid (0.57 g, 1.9 mmol), HOAT (0.28 g, 2.1 mmol), diisopropylethylamine (2.3 mL, 13.2 mmol), methylamine hydrochloride (0.20 g, 2.8 mmol) and dichloromethane (20 mL) was added EDCI (0.51 g, 13.2 mmol). The solution was maintained at room temperature for 6 h, diluted with additional DCM (20 mL), washed with water (20 mL), washed with aqueous HCl (2 x 20 mL, 0.1 N), dried over MgSO₄, filtered and concentrated to afford 2-(4-fluorophenyl)-5-memoxy-N-memylbenzo[b]thiophene-3- carboxamide which was used without further purification. IH NMR (500 MHz, DMSO-D6) δ ppm 8.30 (d, J-4.27 Hz, 1 H), 7.90 (d, J=8.85 Hz, 1 H), 7.60 (dd, J=8.70, 5.34 Hz, 2 H)₅ 7.34 (t, J=8.85 Hz, 2 H), 7.16 (d, J=2.14 Hz, 1 H), 7.07 (dd, J=8.85, 2.44 Hz, 1 H), 3.81 (s, 3 H), 2.74 (<L J=4.58 Hz, 3 H). LCMS: retention time: 2.513 min. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 316 (MH⁺).

2-{4-fluorophenyl)-5-hydroxy-N-methylbenzo[b]thiophene-3-carboxamide. To a suspension containing 2~(4~fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3- carboxamide (0.58 g, 1 ,8 mmol) and DCE (18 mL), was added boron tribromide- methylsulfide complex (2.3 g, 7.4 mmol) in one portion. The mixture was stirred in a closed vessel at 83° C for 9 h under a nitrogen atmosphere, cooled to room temperature and quenched with aqueous HCl (20 mL, 1.0 N). The mixture was concentrated to remove all solvent and water was added (50 mL). The aqueous mixture was extracted with ethyl acetate (3 x 20 mL), dried over MgSCH, filtered and concentrated to afford 2-(4-fluorophenyl)-5-hydroxy-N-methylbenzo[b]thiophene-3- carboxamide as a tan solid which was used without further purification. IH NMR (500 MHz, DMSO-D6) δ ppm 9.56 (s, 1 H), 8.31 (d, J=4.58 Hz, 1 H), 7.78 (d, /=8.55 Hz, 1 H), 7.55 - 7.63 (m, 2 H), 7.29 - 7.37 (m, 2 H), 7.08 (d, /=2.14 Hz, 1 H), 6.91 (dd, /=8.85, 2.44 Hz, 1 H), 2.73 (d, /=4.58 Hz, 3 H). LCMS: retention time: 2.137 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 302 (MH^H).

2-(4-fluor ophenyl)-3-(methylcarb amoyl)b enzo [b] lhioph en-5-yl trifluoromethanesulfonate. A solution containing 2-(4-fluorophenyl)-5-hydroxy-N- methylbenzo[b]thiophene-3-carboxamide (0.47 g, 0.93 mmol), N-

Phenylbis(trifluoromethane)sulfonamide (0.50 g, 1.4 mmol), triethylamine (0.64 mL, 4.6 mmol) and dichloromethane (9.2 mL) was maintained at room temperature for 16 h. The solution was further diluted with dichloromethane (30 mL), washed with saturated, aqueous sodium bicarbonate (20 mL), washed with water (10 mL), dried over MgSO4, filtered and concentrated. Purification on silica gel (0-100% ethyl acetate/hexanes, 45 min gradient) afforded 2-(4-fluorophenyl)-3- (methylcarbamoyl)benzo[b]thiophen-5-yl trifluoromethanesulfonate as a white solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 8.07 (d, /=2,44 Hz, 1 H), 7.85 (d, J-8.54 Hz, 1 H), 7.55 - 7.59 (m, 2 H), 7.30 (dd, J-8.85, 2.44 Hz, 1 H), 7.18 (t, J=8.55 Hz, 2 H), 2.88 (s, 3 H). LCMS: retention time: 2.981 min. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a

Phenomenex-Luna, 10 micron, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 tiM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 mm where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 434 (MH⁺).

3-(2-(4-fluorophenyl)-3-(methyIcarbamoyI)benzolb]thiophen-5-yl)benzoic acid.

To a degassed solution containing 2-(4-fluorophenyl)-3- (methylcarbamoyl)benzo[b]thiophen-5-yl trifluoromethanesulfonate (0.32 g, 0.74 ramolX 3-boronobenzoic acid (0.18 g, 1.1 mmol), cesium carbonate (0.36 g, 1.1 rnmol), dioxane (6.2 mL) and water (1.2 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.016 mmol). The solution was maintained at 95⁰C for 90 min. The solution was cooled to room temperature, concentrated and suspended in ethyl acetate (20 mL) with stirring for Ih. The mixture was filtered, washed with water (3 x 20 mL) and air dried to afford 3-(2-(4- fluorophenyl)-3-(methyicarbamoyl)benzo[b]thiophen-5-yl)benzoic acid as a grey solid which was used without further purification. LCMS: retention time: 2.132 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 406 (MH⁺).

2-(4-fluorophenyi)-N-methyl-5-(3-(2-phenyIpropan-2-yIcarbamoyl)phenyI)benzo

[b]thiophene-3-carboxamϊde. To a solution containing 2-phenylpropan-2 -amine (0.030 g, 0.23 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol), 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and DMF (1.0 mL) was added HATU (0.74 g, 0.20 mmol) in one portion. The solution was maintained at room temperature for 15 h and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 10 min. gradient) afforded 2-(4- fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzo [b]thiophene-3-carboxamide as a white solid. Preparative HPLC: retention time: 8.5 min. IH NMR (500 MHz, DMSO-D6) δ ppm 8.62 (s, 1 H), 8.42 (d, /-4.88 Hz, 1 H), 8.17 (d, J=8.55 Hz₅ 1 H), 8.13 (s, 1 H)₅ 7.99 (s, 1 H), 7.84 - 7.89 (m, 2 H), 7.82 (dd, /=8.55, 1.53 Hz, 1 H), 7.66 (dd, /=8.70, 5.34 Hz, 2 H), 7.59 (t, /=7.78 Hz, 1 H), 7.42 (d, J=7.32 Hz, 2 H), 7.37 (t, /=8.70 Hz, 2 H), 7.30 (t, J=7.63 Hz, 2 H), 7.18 (t, J=7.32 Hz, 1 H), 2.77 (d, /=4.58 Hz, 3 H), 1.71 (s, 6 H), LCMS: retention time: 3.305 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 4.6 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 523 (MH⁺).

2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide. 2-(4- fluorophenyl)-N-methyl- 5 -(3 -( 1 - phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxarm^'de was prepared from 3-(2-(4-fiuorophenyl)-3-(methylcarbamoyl)benzo[b]thioρhen-5- yl)benzoic acid (0.075 g, 0.154 mmol) and 1-phenylcyclopropanamine hydrochloride (0.038 g, 0.22 mmol). IH NMR (500 MHz, DMSO-D6) δ ppm 9.36 (s, 1 H), 8.41 (d, J=4.58 Hz₅ 1 H), 8.22 (s, 1 H), 8.17 (d, J=8.24 Hz, 1 H), 7.98 (d, J=1.53 Hz, 1 H), 7.93 (d, J-7.63 Hz, 1 H), 7.89 (d, J=7.94 Hz, 1 H), 7.83 (dd, J=8.39, 1.68 Hz, 1 H), 7.66 - 7.68 (m, 1 H), 7.65 (d, /=5.19 Hz, 1 H), 7.61 (t, J=7.78 Hz, 1 H), 7.37 (t, J=8.70 Hz, 2 H), 7.29 (t, J=7.63 Hz, 2 H), 7.22 - 7.26 (m, 2 H), 7.15 - 7.19 (m, 1 H), 2.77 (4 /-4.58 Hz₅ S H)₃ 1.31 (d, J-I l.90 Hz, 4 H). LCMS: retention time: 3.250 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 4.6 x 30 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 521

(MH⁺).

2-(4-fluorophenyl)-N-tnethyl-S-(3-(l- phenylcycIobutyIcarbamoyl)phenyl)benzo[bjthiophene-3-carboxaιnide. 2-(4- fluorophenyl)-N-methyl~5-(3-(l - phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1 -phenyl cyclobutanamine hydrochloride (0.041 g, 0.22 mmol). IH NMR (500 MHz, DMSO-D6) δ ppm 9.18 (s, 1 H), 8.42 (d, J=4.58 Hz, 1 H), 8.14 - 8.22 (m, 2 H), 7.97 (s, 1 H)₅ 7.88 (dd, /=16.02, 7.48 Hz, 2 H), 7.82 (d, J=8.54 Hz, 1 H), 7.66 (dd, J-8.24, 5.80 Hz, 2 H), 7.59 (t, J=7.63 Hz, 1 H), 7.52 (d, J=7.63 Hz, 2 H), 7.31 - 7.40 (m, 4 H)₅ 7.21 (t, /=7.32 Hz, 1 H), 2.77 (d, /=4.58 Hz, 3 H), 2.62 - 2.71 (m, 2 H), 2.53 - 2.60 (m, 2 H), 2.02 - 2.11 (m, 1 H)₅ 1.83 - 1.92 (m, 1 H). LCMS: retention time: 3.370 min. LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 30 mm column using a SPD-10AV U V- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of

100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 535 (MH⁺).

I l l

5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyI)-N- methylbenzo[b)thiophene-3-carboxamide. 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-methylbenzo[b]thiophene-3-carboxamide was prepared from 3-(2- (4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 2-methylpropan-2-amine (0.016 g, 0.22 mmol). IH NMR (500 MHz, DMSOD6) δ ppm 8.42 (s, 1 H), 8.16 (s, 1 H), 8.07 (s, 1 H), 7.96 (s, 2 H), 7.82 (s, 3 H), 7.66 (s, 2 H), 7.57 (s, 1 H), 7.37 (s, 2 H), 2.78 (s, 3 H), 1.42 (s, 9 H). LCMS: retention time: 3.218 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6 x 30 mm column using a SPD-I OAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH / 90% H₂O / 10 fflM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 tnM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 461 (MH⁺).

5-(2-chloro-S-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-N-methyIpyrazoIo[l,5-a]pyridine-3- carboxamide. 5-(2-chloro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluoroρhenyl)-6-(N- (2-hydroxyethyl)methylsulfonamido)-N-methylpyrazolo[ 1 ,5-a]pyridine-3- carboxamide was prepared from 5-(2-chloro-5-(isobutylcarbamoyl)phenyl)-2-(4- fluorophenyl)-6-(N-(2-liydroxyethyl)methylsulfonamido)pyrazolo[l_;5-a]pyridine-3- carboxylic acid (0.027 g, 0.045 mmol) and methylamine hydrochloride (0.013 g, 0.18 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 0-100% B (B = 5% H₂CVCH₃CN)/ A (A = 95% H₂O/ CH₃CN), 10 min. gradient) to afford 5-(2- chloro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyI)-6-(N-(2- hydroxyethyl)methylsulfonamido)-N-methylpyrazolo[l,5-a]pyridme-3-carboxamide as a white solid. Preparative HPLC retention time: 6 min. IH NMR (500 MHz, MeOD) δppm 9.01 (s, 1 H)₅ 8.11 (s, 2 H), 7.92 (s, 1 H), 7.84 - 7.91 (m, 3 H), 7.71 (d, /=8.55 Hz, 1 H), 7.24 - 7.30 (m, 2 H)₅ 3.65 (s, 1 H), 3.56 (s, 1 H), 3.30 (d, /=1.22 Hz, 2 H), 3.18 - 3.27 (m, 3 H), 2.82 - 2.91 (m, 4 H), 1.92 (dq, /=13.47, 6.80 Hz, 1 H), 0.99 (d, /=6.71 Hz, 6 H). LCMS retention time: 1.800 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire Cl 8, 5 micron, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 638 (MNa⁺).

5-cyclopropyI-2-(4-fluorophenyl)-6-(N-(2-hydroxyethyI)methyIsulfonamido)-N- methylpyrazolo[l,5~a]pyπdine~3-carboxamide. 5-cyclopropyl-2-(4-fluorophenyl)- 6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methylpyrazolo[l,5-a]ρyridine-3- carboxamide was prepared from 5-cycloρroρyl-2~(4-fluorophenyl)-6-(N-(2- hydroxyethyl) methylsulfonamido)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.013 g, 0.030 mmol) and methylamine hydrochloride (0.008 g, 0.12 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 10 min. gradient) to afford 5-cyclopropyl-2-(4-fiuorophenyl)-6-(N-(2- hydroxyethyl)methylsulfonamido)-N-methylpyrazolo[ 1 , 5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 5.5 min. IH NMR (500 MHz, MeOD) 5 ppm 8.79 (s, 1 H), 7.77 - 7.82 (m, 2 H), 7.42 (s, 1 H), 7.23 - 7.28 (m, 2 H), 4.06 - 4.14 (m, 1 H), 3.72 - 3.79 (m, 1 H), 3.63 - 3.70 (m, 2 H), 3.26 (s, 3 H), 2.87 (s, 3 H), 2.30 - 2.37 (m, 1 H)₅ 1.15 - 1.24 (m, 2 H), 1.02 - 1.10 (m, 1 H), 0.80 (dd, J^8.85, 3.36 Hz, 1 H). LCMS retention time: 1 ,397 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire CIS, 5 micron, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV -Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 468.8 (MNa⁺).

2-(4-fluorophenyl)-6-(N-(2-methoxyethyl)raethylsulfonamido)-N-methyl-5-(3-(2- phenylpropan-2-ylcarbamoyl)phenyl)pyrazoIofl,5-a]pyridine-3-carboxamide.

2-(4-fluorophenyl)-6-(N-(2-methoxyethyl)methylsulfonamido)-N-methyl-5-(3-(2- phenylproρan-2-ylcarbamoyl) phenyl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide was prepared from 2-(4-fluorophenyl)-6-(N-(2-me1hoxyethyl)methylsulfonarnido)-5-(3- (2-phenylpropan-2-ylcarbamoyl)ρhenyl) pyrazolo[l ,5-a]pyridme-3-carboxylic acid (0.032 g, 0.049 mmol) and methylamine hydrochloride (0.014 g, 0.19 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; O.IM ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 10 min. gradient) to afford 2-(4- fluorophenyl)-6-(N-(2-methoxyethyl)methylsulfonamido)-N-methyl-5-(3-(2- phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 8 min.1 H NMR (400 MHz,

CHLOROFORM-i) δ ppm 8.58 (s, 1 H), 8.38 (s, 1 H), 8.25 (s, 1 H), 7.92 - 7.98 (m, 1 H), 7.73 (ddd, J=ILSO, 5.14, 2.89 Hz, 2 H), 7.61 - 7.66 (m, 1 H), 7.52 - 7.58 (m, 1 H), 7.47 (dd, J=8.41, 1.13 Hz, 2 H), 7.24 - 7.34 (m, 10 H), 7.18 - 7.23 (m, 1 H), 5.61 (d, J=4.52 Hz, 1 H), 3.76 - 3.87 (m, 1 H), 3.26 - 3.34 (m, 7 H), 3.18 - 3.26 (m, 3 H), 2.88 (d₅ /=5.02 Hz, 3 H), 2.61 (d, J=15.56 Hz, 1 H), 1,82 (s, 6 H). LCMS retention time: 2.232 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire Cl 8, 5u, Cl 8, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 657.7 (MNa⁺).

6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyI-5-(3-(2- phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide. 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan- 2-ylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 6- (N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-5-(3-(2-phenylρropan-2- ylcarbamoy^pheny^pyrazolotl_jS-ajpyridine-S-carboxylic acid (0.030 g, 0.049 mmol) and methylamine hydrochloride (0.014 g, 0.19 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A - 95% H₂O/ CH₃CN), 10 min. gradient) to afford 6-(N-ethylmethylsulfonamido)-2-(4- fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)ρyrazolo[l_?5- a]pyridine-3-carboxamide as a white solid. Preparative HPLC: retention time: 8.5 min. IH NMR (500 MHz, DMSO-^₆) δ ppm 9.25 (s, 1 H), 8.36 (s, 1 H), 8.05 (q, J=4.37 Hz, 1 H), 8.02 (s, 1 H), 7.89 - 7.95 (m, 3 H), 7.78 (s, 1 H)₅ 7.75 (d, /=7,63 Hz, 1 H)₅ 7.58 (t, J=7.78 Hz, 1 H), 7.40 (d, J=7.32 Hz, 2 H), 7.35 (t, J=8.85 Hz_s 2 H), 7.29 (t, J-7.78 Hz, 2 H), 7.18 (t, J-7.32 Hz, 1 H), 3.52 (s, 1 H), 3.21 (s, 3 H), 3.12 (s, 1 H), 2.77 (d, /=4.58 Hz₅ 3 H), 1.69 (s, 6 H)₅ 0.95 (t, J=IXl Hz, 3 H). LCMS retention time: 2.213 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 fflM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 628 (MH⁺).

2-(4-fluorophenyI)-N-methyI-6-(methyIsuIfonamido)-S-(3-(2-phenylpropan~2- ylcarba ιnoyi)pheny l)py r azolo [1,5-a] py r id in e-3-carb oxamide. 2-(4-fluorophenyl) - N-methyl~6~(methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)ρyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 2-(4- ftuorophenyl)-6-(methylsulfonamido)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyϊ)ρyrazolo[l₅5-a]pyridme-3-carboxylic acid (0.088 g, 0.090 mmol) and methylamine hydrochloride (0.024 g, 0.36 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 10-80% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 20 min. gradient) to afford 2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)-5-(3-(2-phenylproρan-2-ylcarbamoyl)phenyl)pyrazolo[l,5- a]ρyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 14 min. IH NMR (500 MHz, DMSCW₆) δ ppm 9.43 (br. s., 1 H), 8.82 - 8.92 (m, 3 H), 8.46 (s, 3 H), 8.04 (s, 4 H), 7.88 - 7.98 (m, 13 H), 7.69 - 7.78 (m, 7 H), 7.54 - 7.62 (m, 4 H), 7.41 (d, J=7.93 Hz, 7 H), 7.26 - 7.36 (m, 14 H), 7.18 (t, 7=7.17 Hz, 3 H), 2.84 (s, 10 H), 2.71 - 2.80 (m, 11 H), 1.65 - 1.75 (m, 21 H). LCMS retention time: 2.002 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18_} 4.6 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/mm, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 600 (MH⁺).

6-(N-(cyclopropylmethyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3- (I-phenylpropan-Z-ylcarbaraoylJphenyOpyrazololl^S-alpyridine-S-carboxamide.

A mixture containing 2-(4-fluoroρhenyl)-N-methyl-6~(methylsulfonamido)-5-(3-(2- phenylpropan-2-ylcarbamoyl)ρhenyl)pyrazolo[ 1 ,5-a]pyridme-3-carboxamide (0.030 g, 0.050 mmol), bromomethyl)cyclopropane (0.010 g, 0.075 mmol), potassium carbonate (0.028 g, 0.20 mmol) and DMF (0.5 niL) was stirred at 6O⁰C for 15h. The solution was filtered and concentrated to afford a residue containing 6-(N- (cyclopropylmethyl)methylsulfonamido)-2-(4-fiuorophenyl)-N-methyl-5-(3-(2- phenylpropan-2-ylcarbamoyl)phenyl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide which was isolated as a white solid using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M ammonium acetate, 10-80% B (B = 5% H₂CVCH₃CN)/ A (A = 95% H₂O/ CH₃CN), 20 min. gradient). Preparative HPLC retention time: 17 min. IH NMR (500 MHz, DMSO-J₅) δ ppm 9.27 (s, 1 H), 8.35 (s, 1 H), 8.06 (br. s., 2 H), 7.92 (dd, 7-8.70, 5.65 Hz, 3 H), 7.76 - 7.86 (m, 2 H), 7.55 - 7.65 (m, 1 H), 7.33 - 7.42 (m, 4 H), 7.29 (t, J-7.63 Hz, 2 H), 7.15 - 7.25 (m, 1 H), 3.41 (dd, J=14.04, 6.71 Hz, 1 H), 3.21 (s, 3 H), 2.96 (dd, ./=14.19, 7.17 Hz₅ 1 H), 2.77 (d, J=4.27 Hz₉ 3 H), 1.68 (s, 6 H), 0.73 - 0.83 (m, 1 H), 0.34 - 0.44 (m, 1 H), 0.29 (ddd, /-8.16, 4.43, 4.20 Hz, 1 H), 0.01 - 0.11 (m, 1 H), -0.04 (dt, J=9.38₅ 4.62 Hz, 1 H). LCMS retention time: 2.352 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C 18, 5 micron, C 18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%

CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 654 (MH⁺).

6-(N-ethylmeth y lsul fonamid o)-2-(4-fluor oph enyI)-N-methy 1-5- phenylpyrazolo[l,5-a]pyridine-3-carboxamide. 6-(N-ethylmethylsulfonamido)-2- (4-fluorophenyl)-N-methyl-5-phenylpyrazolo[l,5-a]pyridine~3-carboxamide was prepared from 6-(N-ethylmethylsulfonamido)-2-(4-fiuorophenyl)-5- phenylpyrazolo[l,5~a] pyridine-3-carboxyHc acid (0.019 g, 0.042 mmol) and methylamine hydrochloride (0,011 g, 0.16 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M TFA, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A - 95% H₂O/ CH₃CN), 10 min. gradient) to afford 6-(N~ethylmemylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5- phenylpyrazolo[l,5~a]pyπdme-3-carboxarmde as a white solid. Preparative HPLC retention time: 7 min. IH NMR (400 IH NMR (400 MHz, CHLOROFORM-^ δ ppm 8 56 (s, 1 H), 8.32 (s, 1 H), 7.67 - 7.77 (m, 2 H), 7 54 (d, J=I 01 Hz, 1 H), 7 52 (d, J=I.51 Hz, 1 H), 7.40 - 7.50 (m, 3 H), 7.20 - 7.30 (m, 4 H), 5.54 (d, J=4.02 Hz, 1 H), 2.81 - 2.93 (m, 3 H), 2.70 - 2.81 (m, 3 H), 1.16 (t, J=7.15 Hz, 3 H). LCMS retention time: 1.443 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Xterra, 7 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 mm, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC m electrospray mode, m/z 466.9 (MH^H).

5-cyclohexyl-6-(N-ethyImethylsulfonainϊdo)-2-(4-fluorophenyϊ)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide. 5-cyclohexyl-6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5-a]pyπdme-3- carboxamide was prepared from 5-cyclohexyl-6-(N-ethylmethylsulfonamido)-2-(4- fluorophenyl)pyrazolo[l,5-a]pyπdine-3-carboxyhc acid (0 018 g, 0.039 mmol) and methylamine hydrochloride (0.011 g, 0.16 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M TFA, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 mm. gradient) to afford 5-cyclohexyl-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)- N-methylpyrazolo[ 1 , 5 -a]pyπdme-3 -carboxamide Preparative HPLC retention time: 10 mm. IH NMR (400 MHz, CHLOROFORM-^ δ ppm 8.47 (s, 1 H), 8.31 (s, 1 H), 7.63 - 7.75 (m, 2 H), 7.22 - 7.28 (m, 5 H), 3.84 (dq, /=14.05, 7.03 Hz, 1 H), 3.57 (dq, /=14.02, 7.12 Hz, 1 H), 3.03 - 3.07 (m, 3 H), 2.90 - 2.99 (m, 7-11.86, 11.86, 3.39, 3.26 Hz, 1 H), 2.88 (d, /-4.77 Hz, 3 H), 2.00 (d, /=13.05 Hz, 1 H), 1.89 (d, J=I 1.29 Hz, 2 H), 1.73 - 1.85 (m, 2 H), 1.54 - 1.64 (m, 2 H), 1.35 - 1.48 (m, 3 H), 1.20 - 1.27 (m, 3 H). LCMS retention time: 1.577 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Xterra, 7 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 473 (MH⁺).

5-cyclopentyI-6-(N-ethylmethylsuIfonamido)-2-(4-fluorophenyl)-N- methylpyrazolo [ 1 ,5-a] pyridine-3-carboxamide. 5 -cyclopentyl-6-(N- ethylmethylsulfonamido)~2-(4-fluorophenyl)-N-methylpyrazolo[l,5-a]pyridine-3- carboxamide was prepared from 5-cyclohexyl-6-(N-ethylmethylsulfonamido)-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carboxylic acid (0.015 g, 0.034 mmol) and methylamine hydrochloride (0.009 g, 0.13 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 10-100% B (B - 5% H₂CVCH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 5-cyclopentyl-6-(N-ethylmethylsulfonamido)-2-(4-fiuorophenyl)~ N-methylpyrazolo[ 1,5-a] ρyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 9 min. IHNMR (400 MHz, CHLOROFORM-^) δ ppm 8.42 - 8.50 (m, 1 H), 8.30 - 8.42 (m, 1 H), 7.64 - 7.73 (m, 2 H), 7.21 - 7.33 (m, 2 H), 5.51 (br. s., 1 H), 3.83 (dd, /=13.80, 7.03 Hz, 1 H), 3.56 - 3.69 (m, 1 H), 3,41 (d, /=8.53 Hz, 1 H), 3.00 - 3.12 (m, 3 H), 2.87 (d, J=4.77 Hz₁ 3 H), 2.25 (br. s._; 1 H), 2.11 (br. s., 1 H), 1.95 (br. s., 2 H), 1.75 (br. s., 6 H), 1.19 - 1.31 (m, 3 H). LCMS retention time: 1.500 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Xterra, 7 micron, CIS, 3.0 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H₂O / 10 raM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 459 (MH⁺).

5-cyclopropyl-6-(N-ethylraethylsulfonamido)-2-(4-fluoropheny])-N- methy(pyrazolo[l,5-a]pyridme-3-carboxamide. To a degassed solution containing

6~(N-ethylmethylsulfonamido)-2-(4-fiuorophenyl)-3-

(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl trifluoromethanesulfonate (0.050 g, 0.093 mmoϊ), cyclopropylboronic acid (0.012 g, 0.14 mmol), Potassium phosphate tribasic monohydrate (0.69 g, 0.33 mmol), tricyclohexylphosphiiie (0.260 mg, 0.93 μmol), toluene (0.9 mL) and water (0.08 niL) was added palladium acetate (1.0 mg, 4.64 μmol). The solution was maintained at 95°C for 2 h. The solution was filtered to remove solids and concentrated to afford a residue containing 5-cyclopropyl-6-(N- ethylmethylsulfonamido)-2-(4-fluoroρhenyl)-N-methylpyrazolo[l,5-a]pyridine-3- carboxamide. The compound was isolated as a white solid using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient). Preparative HPLC retention time: 8.5 min. IH NMR (400 MHz, CHLOROFORM-*/) δ ppm 8.50 (s, 1 H), 7.84 (s, 1 H), 7.62 - 7.74 (m, 2 H), 7.17 - 7.29 (m, 2 H), 5.52 (br. s., 1 H), 3.90 (br. s., 1 H), 3.70 (d, J=7.78 Hz, 1 H), 3.08 (s, 3 H), 2.86 (d, J=4.77 Hz, 3 H), 2.23 («, ./=8.31, 5.24 Hz, 2 H), 1.27 (t, J=7.15 Hz, 3 H)₉ 1.19 (ddd, J-8.22, 3.07, 1.51 Hz, 2 H), 1.13 (d, J=14.31 Hz, 1 H). LCMS retention time: 1.322 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Xterra, 7 micron, C 18, 3.0 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% methanol / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% methanol/ 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 430.8 (MH⁺).

6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-5-(5-(l-(4- fluoropheny^cyclopropylcarbamoylJ-l-methylphenyO-N-methylpyrazoloJl-S- a]pyridine-3-carboxamide. 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-5~ (5-(l-(4-fluoroρhenyl) cyclopropylcarbamoyl)-2-methylphenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(6-(N- ethylmethylsulfonamido)-2-(4-fluoroρhenyl)-3-(methylcarbamoyl)pyrazolo[l,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.024 g, 0.046 mmol) and l-(4- fluorophenyl)cyclopropanamine hydrochloride (0.013 g, 0.069 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 6-(N- ethyImethylsulfonamido)-2-(4-fiuorophenyl)-5-(5-(l~ (4fluorophenyl)cyclopropylcarba moyl)-2-methylphenyl)-N-methylρyrazolo[ 1 ,5- a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 8.5 min. IH NMR (400 MHz, CHLOROFORM-tf) δ ppm 8.54 (s, 1 H), 8.29 (s, 1 H), 7.82 (br. s., 2 H), 7.65 - 7.77 (m, 2 H), 7.40 (d, J-7.78 Hz₅ 2 H), 7.31 - 7.38 (m, 3 H)₁ 7.22 - 7.30 (m, 4 H), 6.90 - 7.00 (m, 2 H), 5.55 (d, J=4.77 Hz, 1 H), 3.42 (br. s., 1 H), 3.00 - 3.12 (m, 2 H), 2.78 - 2.90 (m, 4 H)₅ 2.34 (s, 3 H), 1.62 (br. s., 2 H), 1.25 - 1.37 (m, 5 H), 1.08 (br. s._} 3 H). LCMS retention time: 1.920 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18_> 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 mm where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate, MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 658 (MH⁺).

2-(4-fluorophenyl)-5-(5-(l-(4-fluorophenyϊ)cyclopropylcarbamoyI)-2- methylphenyl)~N~methylpyrazolo[l,5-a]pyridine-3-carboxamide. 2-(4- fluorophenyl)-5 -(5 -( 1 - (4-fluorophenyl)cyclopropylcarbamoyl) -2-methylphenyl) -N- methylpyrazolo[l_I5-a]ρyridine-3-carboxamide was prepared from 3-(2-(4- fluoroρhenyl)-3 -(methylcarbamoyl)pyrazolo [ 1 , 5 -a] pyridin- 5 -yl)~4-methylbenzoic acid (0.016 g, 0.040 mmol) and l-(4-fluoroρhenyl)cycloρropanamine hydrochloride (0.011 g, 0.059 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 10-100% B (B = 5% H₂CVCH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 2-(4-fluorophenyl)-5-(5-(l-(4-fluorophenyl)cycloproρylcarbamoyl)-2- methylphenyl)-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 10.5 min. IH NMR (400 MHz, DMSO-^₆) δ ppm 9.24 (s, 1 H)₁ 8.84 (d, J=7.03 Hz, 1 H), 7.83 - 7.96 (m, 5 H)₅ 7.75 (s, 1 H), 7.47 (d, 7=8.03 Hz, 1 H), 7.26 - 7.38 (m, 4 H), 7.05 - 7.16 (m, 3 H), 2.78 (d, /=4.77 Hz, 3 H), 2.37 (s, 3 H), 1.26 (d, J-6.27 Hz₅ 4 H). LCMS retention time: 2.533 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH⁺).

2-(4-fluorophenyl)-N-methyI-5-(2-methyl-5-(l- phenyIcycϊobutyIcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide. 2-

(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-phenylcyclobutylcarbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4- fiuorophenyl)-3-(methylcarbamoyl)pyrazolo[ 1 ,5 -a]pyridm~5-yl)-4-methylbenzoic acid (0.024 g, 0.059 mmol) and 1-phenylcyclobutanamine hydrochloride (0.016 g, 0.089 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A - 95% H₂O/ CH₃CN), 15 min. gradient) to afford 2-(4- fluorophenyl)-N-methyl-5-(2-methyl-5-(l~phenylcyclobutylcarbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 11 min. IH NMR (400 MHz, CHLOROFORM-J) δ ppm 8.52 (d, J=7.03 Hz, 1 H), 8.29 (s, 1 H), 7.67 - 7.79 (m, 4 H), 7.54 (d, J=7.78 Hz, 2 H), 7.32 - 7.43 (m, 3 H), 7.20 - 7,32 (m, 6 H), 6.94 (d, J=7.03 Hz, 1 H), 6.80 (s, 1 H), 5.66 (d, J=4.27 Hz, 1 H), 2.88 (d, J=4.77 Hz, 3 H), 2.75 (t, /=7.78 Hz, 4 H), 2.38 (s, 3 H), 2.11 - 2.24 (m, 1 H), 1.95 (dt, J=I 1.48, 7.94 Hz, 1 H). LCMS retention time: 1.870 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 rain, and an analysis time of 3 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA, MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH⁺).

Example 24

2-(4-fluorophenyl)-N,7-diraethyl-5-(2-methyl-S-(l- phenylcyclopropylcarbamoyI)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide.

Following the procedure for preparing 4-fluoro-2-(4-fluoroρhenyl)~N-methyl-5-(2- methyl-5 -( 1 -phenylcyclopropylcarbamoyl)phenyl)pyrazolo[ 1 ,5 -a]pyridine-3 - carboxamide (Example 25), 2-(4-fluorophenyl)-N,7-dimethyl-5-(2-methyl-5-(l - phenylcyclopropylcarbamoyl)phenyl)pyrazolo[ 1 ,5-a]pyridine-3 -carboxamide was prepared from 3-(2-(4-fluorophenyl)-7-methyl-3-(methylcarbamoyl)pyrazolo[ 1 ,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.022 g, 0.053 mmol) and 1- phenylcyclopropanamine hydrochloride (0.013 g, 0.079 mmol). The residue thus obtained was purified using preparative HPLC (Waters- Xbridge, 50 x. 100 mm, 5 micron, C18 column; 0.1M TFA, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 2-(4-fluorophenyl)-N,7-dimethyl-5-(2- methyl-5 -( 1 -phenylcyclopropy lcarbamoyl)phenyl)pyrazolo [1,5 -a]pyridme-3 - carboxamide as a white solid. Preparative HPLC retention time: 11.5 min. IH NMR (400 MHz, CHLOROFORM-^) δ ppm 8.23 (d, J=I .25 Hz, 1 H), 7.69 - 7.82 (m, 4 H), 7.39 (d, J=8.03 Hz_> 1 H), 7.29 - 7.36 (m, 4 H), 7.23 - 7.29 (m, 6 H), 7.17 - 7,23 (m, 1 H), 7.04 (s, 1 H), 6.82 (s, 1 H), 5.66 (d, J=4.52 Hz, 1 H), 2.87 (d, J=5.02 Hz, 4 H), 2.84 (s, 3 H), 2.40 (s, 3 H), 1.34 - 1.46 (m, 4 H). LCMS retention time: 2.413 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire Cl 8, 5 micron, Cl 8, 4.6 x 50 mm column using a SPD-I OAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CHjCN / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH⁺).

tert-butyl δ-chloro-β-fluoro-Σ^-fluoropheny^pyrazoloIl^S-ajpyridine-S- carbonyl(methyl)carbamate and tert-butyl 5-chloro-4-fluoro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carbonyl(methyl)carbamate. tert-butyl 5-chloro-6-fluoro-2-(4-fluorophenyl)pyrazolo[ 1 ,5-a]pyridine-3- carbonyl(methyl)carbamate and tert-butyl 5-chloro-4-fluoro-2-(4- fluorophenyl)pyrazolo[ 1 ,5 -a]pyridine-3 -carbonyl(methyl)carbamate were prepared as a residue containing a mixture of regioisomers starting from 4-chloro-3- fiuoropyridine (2.0 g, 15.2 mmol). Isolation on silica gel (0-80% ethyl acetate/hexanes, 60 min gradient) afforded tert-butyl 5-chloro-6-fluoro-2-(4- fluorophenyl)pyrazolo[l_f5-a]pyridine-3-carbonyl(methyl)carbamate as the first eluting isomer and tert-butyl 5-chloro-4-fluoro~2-(4~fluorophenyl)pyrazolo[ 1 ,5- a]pyridine-3-carbonyl(methyl)carbamate as the second eluting isomer which was favored in a 2.2/1 ratio. Each isomer was an off white solid, tert-butyl 5-chloro-6-fluoro-2-(4-fluorophenyl)pyrazolo[ 1 ,5-a]pyridine-3-carbonyl (methyl)carbamate: IH NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.48 (d, J=3.76 Hz, 1 H), 7.93 (d, J=7.28 Hz, 1 H), 7.65 (dd, J-8.66, 5.40 Hz, 2 H), 7.15 (t, J-8.66 Hz, 2 H), 3.26 (s, 3 H), 1.11 (s, 9 H). LCMS retention time: 2.681 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 422 (MH⁺). tert-butyl 5-chloro-4-fiuoro-2- (4-fluorophenyl)pyrazolo[ 1 ,5-a]pyridine-3-carbonyl (metliyl)carbamate: 1 H NMR (400 MHz, CHLOROFORM-φ δ ppm 8.26 (dd, /=7.28, 1.00 Hz₅ 1 H), 7.71 (dd, /==8.91, 5.40 Hz, 2 H), 7.15 (t, /-8.66 Hz, 2 H), 6.80 - 6.89 (m, 1 H), 3.34 (s, 3 H), 1.15 (s, 9 H). LCMS retention time: 2.625 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C 18, 5 micron, C 18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10%

CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 422 (MH⁺).

3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl) pyrazoIo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid. To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fiuorophenyl)pyrazolo[l ,5-a]ρyridine-3- carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4_}4_J5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95⁰C for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2,0 mL). Water was added (10 rnL) and the aqueous portion was extracted with ethyl acetate (2 x 15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(memyl)carbamoyl)-4-fiuoro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C 18, 5 micron, Cl 8, 4.6 x 50 mm column using a SPD- 1 OAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃CN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 522 (MH⁺).

3~(4~fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazoIo[l₅5-a]pyridin-5-yl)-

4-methylbenzoic acid. To a solution containing 3-(3-(tert~ butoxycarbonyl(methyl)carbamoyl)-4-fiuoro-2-(4-fiuorophenyl)pyrazolo[l,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.070 g, 0.13 mmol) and dicMoromethane (8.0 mL) was added TFA (0.84 mL, 10.9 mmol) at room temperature. The solution was maintained for 15 min and concentrated to dryness to afford 3-(4-fluoro-2-(4- fluorophenyl)-3 -(methylcarbamoyl)pyrazolo[ 1 ,5 -a]pyridin- 5 -yl)-4~methylbenzoic acid as an off white solid which was used without further purification, LCMS retention time: 1.825 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Sunfire C 18, 5 micron, CIS, 4.6 x 50 mm column using a SPD- 1 OAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CHjCN / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃CN / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 444 (MNa^1"),

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l- phenylcyclopropyIcarbamoyl)phenyl)pyrazoIo[l,5-a]pyridine-3-carboxamide.

To a solution containing 1-phenylcyclopropanamine hydrochloride (0.030 g, 0.18 mmol), diisopropylethylamine (0.16 niL, 0.95 mmol), 3-(4-fiuoro-2-(4- fluorophenyl)-3 -(methylcarbamoyl)pyrazolo [1,5 -a]pyridin- 5 -yl)-4-methylb enzoic acid (0.050 g, 0.12 mmol) and DMF (0.8 mL) was added HATU (0.09 g, 0.24 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 10-100% B (B ■= 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 4- fluoro-2-(4-fluorophenyl)-N-memyl-5-(2-methyl-5-(l- phenylcyclopropylcarbamoyl)ρhenyl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 9.0 min. IH NMR (400 MHz, CHLOROFORM-^ δ ppm 8.35 (d, ./=6.78 Hz, 1 H), 7.81 - 7.90 (m, 2 H), 7.76 (d, J=7.78 Hz, 1 H)₅ 7.72 (s, 1 H), 7.40 (d, J-8.03 Hz, 1 H), 7.29 - 7.37 (m, 4 H), 7.13 - 7.24 (m, 3 H), 6.90 (s, 1 H), 6.73 (t, J=6.65 Hz₅ 1 H), 5.90 (d, J=4.52 Hz, 1 H), 2.97 (d, J=4.77 Hz, 3 H), 2.32 (s, 3 H), 1.39 (br. s., 4 H). LCMS retention time: 1.975 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Xbridge, 5 micron, C18, 4.6 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% CH₃CN / 95% H₂O / 10 mM ammonium acetate and solvent B was 5% H₂O / 95% CH₃CN / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH⁺).

6-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l- phenylcyclopropylcarbamoyI)phenyl)pyrazolo[l,5~a]pyridine-3-carboxamide. 6-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-phenylcyclopropyl carbamoyl) phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(6- flυoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-4- methylbenzoic acid (0.024 g, 0.059 mmol) and 1-phenylcyclopropanamine hydrochloride (0.015 g, 0.089 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 10-100% B (B = 5% H2O/CH3CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 6-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l- phenylcyclopropylcarbamoyl)phenyl)pyrazolo [1 ,5 ~a]pyridine-3 -carboxamide as a white solid. Preparative HPLC retention time: 10.5 min. IH NMR (400 MHz, CHLOROFORM-tf) 5 ppm 8.49 (d, J=4.02 Hz, 1 H), 8.31 (d, J=7.53 Hz, 1 H), 7.84 (dd, /=8.03, 1.76 Hz, 1 H), 7.66 - 7.74 (m, 3 H), 7.40 (d, /=8.03 Hz₅ 1 H), 7.29 - 7.37 (m, 4 H)₅ 7.24 - 7.27 (m, 1 H), 7.20 (t, J=6.02 Hz, 1 H), 6.89 (s, 1 H), 5.56 (d, /=4.27 Hz, 1 H), 2.86 (d, /-4.77 Hz, 3 H), 2.32 (s, 3 H), 1.40 (d, /=9.03 Hz, 4 H). LCMS retention time: 2,535 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x. 50 mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH⁺).

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropyϊcarbamoyl)phenyϊ)pyrazoIo[l,5-a]pyridine-3-carboxamide. 4- fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(pyridin-2~ yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide was prepared from 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l ,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.065 g, 0.154 mmol) and l-(pyridin-2- yl)cycloproρanamine dihydrochloride (0.032 g, 0.154 mmol). The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M ammonium acetate, 10-100% B (B - 5% H₂O/CH3CN)/ A (A = 95% H₂O/ CH₃CN), 20 min. gradient) to afford 4-fluoro-2-(4-fluorophenyl)-N-methyl-5- (2-methyl~5-(l -(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[ 1 ,5-a]pyridine- 3-carboxamide as a white solid. Preparative HPLC: retention time: 9.5 min. IH NMR (400 MHz, CHLOROFORM-rf) δ ppm 8.48 (d, J=4.02 Hz, 1 H), 8.37 (d, J=7.03 Hz, 1 H), 7.78 - 7.90 (m, 4 H), 7.60 (td, J=7.78, 1.76 Hz₅ 1 H)₅ 7.44 (d, J=8.03 Hz, 1 H), 7.38 (d, J=7.78 Hz, 1 H), 7.13 - 7.22 (m, 2 H), 7.04 - 7.13 (m, 2 H), 6.76 (t, /-6.78 Hz, 1 HX 5.87 (d, J=4.52 Hz, 1 H), 2.97 (d, J=5.02 Hz, 3 H), 2.35 (s, 3 H), 1.69 - 1.80 (m, 2 H), 1.37 - 1.48 (m, 2 H). LCMS retention time: 1.642 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% methanol / 90% water / 10 mM TFA and solvent B was 10% water / 90% methanol / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 538 (MH⁺).

4-flαoro-5-(3-fluoro-2-methyl-S-(l~phenylcyclopropyIcarbamoyl)phenyl)-2-(4- fluorophenyl)~N-methylpyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing 1-phenylcyclopropanamine hydrochloride (0.059 g, 0,027 mmol), diisopropylethylamine (0.04 mL, 0.22 mmol), 3-fluoro-5-(4-fluoro-2-(4- fluoroρhenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.012 g, 0.027 mmol) and DMF (0.19 mL) was added HATU (0.021 g, 0.055 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 20 min. gradient) afforded 4- fluoro-5-(3-fluoro-2-methyl-5-(l-phenylcycloproρylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 15.0 min. 1 H NMR (400 MHz₁ CHLOROFORM- d) δ ppm 8.36 (d, J-7.03 Hz, 1 H), 7.80 - 7.89 (m, 2 H), 7.56 (d, J=9.79 Hz, 1 H), 7.51 (s, 1 H), 7.28 - 7.36 (m, 4 H), 7,13 - 7.25 (m, 3 H), 6.91 (s, 1 H), 6.72 (t, /=6.78 Hz, 1 H), 5.85 (d, J=4.27 Hz, 1 H), 2.97 (d, J=4.77 Hz, 3 H), 2.23 (s, 3 H)₅ 1.38 (s, 4 H). LCMS retention time: 2,437 min. LC data was recorded on a Shimadzu LC- IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 niM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 555 (MH⁺).

4-fluoro-S-(3-fluoro-2-methyl-S-(l-(pyridm-2-yl)cyclopropylcarbamoyl)phenyl)- 2-(4~fluorophenyl)-N-methyIpyrazololl,5-a]pyricline-3-carboxamide. To a solution containing 1 -(pyridin-2-yl)cyclopropanamme dihydrochloride (0.070 g, 0.033 mmol), diisopropylethylamine (0.04 mL, 0.22 mmol), 3-fluoro-5-(4-fluoro-2~ (4-fluorophenyl)~3-(methylcarbamoyl)pyrazolo[l_j5-a]pyridin-5-yl)-4-methylbenzoic acid (0.012 g, 0.027 mmol) and DMF (0.19 mL) was added HATU (0.021 g, 0.055 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 20 min. gradient) afforded 4- fluoro- 5-(3 -fluoro-2-methyl- 5 -( 1 -(p yr idin-2-yl)cyclopropylcarb amoyl)phenyl)-2 -(4- fluorophenyl)-N-methyl pyrazolo[l,5-a]pyridine-3-carboxamide as a white solid, Preparative HPLC retention time: 11.0 min. 1 H NMR (400 MHz, CHLOROFORM- d) δ ppm 8.44 - 8.53 (m, 1 H), 8.38 (d, J-7.03 Hz, 1 H)₅ 7.80 - 7.90 (m, 2 H), 7.55 - 7.67 (m, 3 H), 7.36 (d, J=8.03 Hz, 1 H), 7.31 (s, 1 H), 7.14 - 7.22 (m, 2 H)₁ 7.10 (ddd, j=7.47, 4.96, 1.13 Hz, 1 H), 6.74 (t, J=6.78 Hz, 1 H), 5.87 (d, /=4.77 Hz, 1 H), 2.97 (d, J=4.77 Hz, 3 H), 2.25 (s, 3 H), 1.66 - 1.73 (m, 2 H), 1.38 - 1.46 (m, 2 H). LCMS retention time: 1.828 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃ OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. ra/z 556 (MH⁺).

4-fluoro-5-(3-fluoro-2-methyl-5-(l-(3-methyl-l,2,4-osadiazol-S- yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5- a]ρyridine-3-carboxamide. To a solution containing 1 -(3 -methyl- 1,2,4-oxadiazol- 5-yl)cycloproρanaminiυm 2,2,2-trifluoroacetate (0.021 g, 0.083 mmol), diisopropylethylamine (0.08 mL, 0.51 mmol)., 3-fluoro-5-(4-fluoro-2-(4- fluorophenyl)-3-(methylcarbamoyl)ρyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.064 mmol) and DMF (0.43 mL) was added HATU (0.048 g, 0.13 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; OJM ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) afforded 4- fluoro-5-(3-fluoro-2-methyl-5-(l-(3-methyl-l,2,4-oxadiazol-5-yl) cyclopropylcarbamoyl)phenyl)-2"(4-fluorophenyl)-N-methylρyrazolo[l,5-a]pyridine- 3-carboxamide as a white solid. Preparative HPLC retention time: 8.5 min. IH NMR (400 MHz, CHLOROFORM-cf) 5 ppm 8.35 (d, /=7.03 Hz, 1 H), 7.77 - 7.88 (m, 2 H), 7.61 (dd, J=9.54, 1.51 Hz, 1 H), 7.54 (s, 1 H), 7.27 - 7.33 (m, 1 H), 7.13 - 7.22 (m, 2 H), 6.71 (t, J=6.65 Hz, 1 H), 5.92 (d, J=4.52 Hz, 1 H), 2.97 (d, J-5.02 Hz, 3 H), 2.32 (s, 3 H), 2.22 (s, 3 H), 1.77 - 1.87 (m, 2 H), 1.55 - 1.65 (m, 2 H). LCMS retention time: 2.137 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 561 (MH⁺).

4-fluoro~2-(4-fluorophenyl)-5-(4-methoxy-2-methy!-5-(l-(3-methyH_?2,4- oxadiazol-S-ylJcyclopropylcarbamoy^pheny^-N-methylpyrazololl^-alpyridine-

3-carboxamide. To a solution containing l-β-methyl-i^-oxadiazol-S- yl)cyclopropanamimum 2,2,2-trifluoroacetate (0.024 g, 0.095 mmol), diisopropylethylamine (0,1O mL, 0.56 mmol), 5-(4-fluoro-2-(4-fiuorophenyl)-3- (methylcarbamoyl)pyr azolo [ 1 , 5 -a] pyridin-5 -yl)-2-methoxy-4-methylbenzoic acid (0.033 g, 0.073 mmol) and DMF (0.49 mL) was added HATU (0.056 g, 0.15 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M ammonium acetate, 0-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) afforded A- fluoro-2-(4-fiuorophenyl)-5-(4-methoxy-2-methyl-5-(l -(3-methyl-l ,2,4-oxadiazol-5- yl)cyclopropylcarbamoyl)ρhenyl)-N~methylpyrazolotl,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 9.0 min. IH NMR (400 MHz, CHLOROFORM-^) δ ppm 8.57 (s, 1 H), 8.34 (d, /=7.03 Hz, 1 H), 8.13 (s, 1 H), 7.79 - 7.92 (m, 2 H), 7.10 - 7.21 (m, 2 H), 6.97 (s, 1 H), 6.73 (t, 7=6.78 Hz, 1 H), 5.89 (d, /=4,52 Hz, 1 H), 4.07 (s, 3 H)₇ 2.97 (d, ./=5.02 Hz, 3 H), 2.34 (s, 6 H), 1.77 - 1.88 (m, 2 H), 1.50 - 1.63 (m, 2 H). LCMS retention time: 2.533 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 573 (MH⁺).

S-(5~(l~cyclohexyIcyclopropylcarbanioyl)-4-methoxy-2-raethylphenyl)-4-fluoro- 2-(4-fluorophenyl)-N-methylpyrazoIo[l,5-a]pyridine-3-carboxamide. To a solution containing 1-cyclohexylcyclopropanamine hydrochloride (0.020 g, 0.12 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro-2-(4- fluorophenyl)- 3 -(methylcarbamoyl)pyrazolo[ 1 , 5 -a]ρ yridin- 5 -yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 0-100% B (B - 10% H₂O/CH₃OH)/ A (A = 90% H₂O/ CH₃OH), 12 min. gradient, analysis time 20 min.) afforded 5-(5-(l-cyclohexylcyclopropylcarbamoyl)- 4-methoxy-2-methylphenyl)-4-fluoro-2-(4- fluorophenyl)-N-methylpyrazolo [1,5- a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 13.0 min. IH NMR (400 MHz, CHLOROFORM-cf) δ ppm 8.35 (d, J-7.03 Hz, 1 H)₅ 8.02 - 8.14 (m, 2 H), 7.84 (dd, /=8.53, 5.27 Hz, 2 H), 7.17 (t, J=8.66 Hz, 2 H), 6.94 (s, 1 H), 6.76 (t, J-6.78 Hz, 1 H), 5.97 (br. s._} 1 H), 4.04 (s, 3 H), 2.98 (d, J-4.77 Hz, 3 H), 2,33 (s, 3 H), 2.18 (br. s., 1 H), 1.87 (47=11.80 Hz, 2 H)₉ 1.76 (d, J=I 2.55 Hz, 2 H), 1.20 - 1.31 (m, 2 H), 1.18 (br. s., 1 H), 1.10 (d, 7=2.76 Hz, 2 H), 1.08 (br. s., 1 H), 0.77 - 0.90 (m, 4 H). LCMS retention time: 2.726 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 πiM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 573 (MH⁺).

4-fluor o-2-(4-fluorop henyl)-5-(4~methoxy-2-methyl-5-(l - methylcyclopropylcarbamoylJphenyl^N-methylpyrazolofljS-alpyridine-S- carboxamide. To a solution containing 1-methylcycloproρanamine hydrochloride (0.012 g, 0.12 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro-2- (4-fluorophenyl)-3 -(methylcarbamoyl)pyrazolo[ 1 ,5 -a]pyridin-5 -yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 0-100% B (B = 10% H₂O/CH₃OH)/ A (A - 90% H₂O/ CH₃OH), 12 min. gradient, analysis time 20 min.) afforded 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy- 2-methyl-5 -( 1 -methylcyclopropylcarbamoylJphenyO-N-methylpyrazolof 1,5- a]ρyridine-3~carboxamide as a white solid. Preparative HPLC retention time: 11.7 min. IH NMR (400 MHz, CHLOROFORM-*/) δ ppm 8.35 (d, J-7.03 Hz, 1 H), 8.14 (s, 1 H), 8.10 (s, 1 H), 7.79 - 7.89 (m, 2 H), 7.12 - 7.21 (m, 2 H), 6.92 (s, 1 H), 6.75 (t, J=6.78 Hz, 1 H), 5.97 (d, ./=3,76 Hz, 1 H), 4.03 (s, 3 H), 2.98 (d, 7=5.02 Hz, 3 H), 2.32 (s, 3 H), 1.50 (s, 3 H), 0.82 - 0.89 (m, 2 H), 0.68 - 0.78 (m, 2 H). LCMS retention time: 2.232 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH MO mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH⁺).

4-fluoro-2-(4-fluorophenyl)~5-(S-(l»(4-fluorophenyl)cyclopropykarbamoyl)-4~ methoxy-Z-methylphenylJ-N-methylpyrazolotl_jS-alpyridine-S-carboxamide. To a solution containing l-(4~fluorophenyl)cycloρropanamine hydrochloride (0.022 g, 0.12 mmol), diisopropylethylamme (0.12 mL, 0.71 mmol), 5-(4-fiuoro-2~(4- fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B - 10% H2O/CH3OH)/ A (A = 90% H₂O/ CH₃OH)₅ 12 min. gradient, analysis time 20 min.) afforded 4-fluoro-2-(4-fluorophenyl)-5 -(5 -( 1 -(4- fLuorophenyl)cycloρropyϊcarbamoyl)-4-methoxy-2-methylphenyl)-N- methylpyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 12.1 min. IH NMR (400 MHz, CHLOROFORM-^ δ ppm 8.46 (s, 1 H), 8.34 (d, J=7.03 Hz, 1 H), 8.10 (s, 1 H), 7.79 - 7.90 (m, 2 H), 7.28 - 7.37 (m, 2 H), 7.11 - 7.23 (m, 2 H)₅ 6.91 - 7.03 (m, 3 H), 6.74 (t, J=6.78 Hz, 1 H), 5.93 (d, /=4.52 Hz, 1 H), 4.06 (s, 3 H), 2.97 (d, J=5.02 Hz, 3 H), 2.33 (s, 3 H), 1.35 (dd, ./=6.15, 1.88 Hz, 4 H). LCMS retention time: 2.438 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 585 (MH⁺).

5-(5-(bi(cycloprop)ylcarbamoyI)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4- fiuorophenyl)-N-raethylpyrazolo[l,5-a]pyridme-3-carbosamide. To a solution containing bi(cyclopropan)-! -amine hydrochloride (0.015 g, 0.12 mmol), diisopropylethylamine (0.12 niL, 0.71 mmol), 5-(4-fluoro-2-(4-fluorophenyl)-3- (methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-2-methoxy-4-methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 niL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C 18 column; 0.1 M TFA, 0- 100% B (B = 10% H₂O/CH₃OH)/ A (A - 90% H₂O/ CH₃OH), 12 min. gradient, analysis time 20 min.) afforded 5-(5-(bi(cycloprop)ylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4- fluorophenyl)-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 11.7 mm. IH NMR (400 MHz, CHLOROFORM- d) 5 ppm 8.35 (d, J=7.03 Hz, 1 H), 8.09 - 8.20 (m, 2 H), 7.79 - 7.89 (m, 2 H), 7.12 - 7.23 (m, 2 H), 6.93 (s, 1 H), 6.76 (t, /=6.78 Hz, 1 H), 5.96 (br. s., 1 H)₁ 4.03 (s, 3 H), 2.98 (d, J=5.02 Hz, 3 H), 2.33 (s, 3 H), 1.53 (tt, J=8.28, 5.02 Hz, 1 H), 0.78 - 0.84 (m, 2 H), 0.67 - 0.75 (m, 2 H)₅ 0.41 - 0.50 (m, 2 H)₅ 0.18 - 0.28 (m, 2 H). LCMS retention time: 2.405 mm. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 niM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 531 (MH"^").

4-fluoro-2-(4-fluorophenyl)-5-(5-(l-isopropylcyclopropylcarbamoyl)-4-methoxy- 2~methyϊphenyl)-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing 1-isopropylcyclopropanamine hydrochloride (0,016 g, 0.12 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro~2-(4-fluorophenyl)-3- (methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-2-methoxy-4-methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B = 10% H2O/CH₃OH)/ A (A = 90% H₂O/ CH₃OH)₅ 12 min. gradient, analysis time 15 min.) afforded 4-fluoro-2-(4-fluorophenyl)-5-(5-(l-isopropylcyclopropylcarbamoyl)-4- methoxy-2-methylphenyl)-N-methyϊpyrazolo[ 1 ,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 12.1 min. IH NMR (400 MHz, CHLOROFORM-^ δ ppm 8.35 (d, 7=7.03 Hz, 1 H), 8.06 (s, 2 H), 7.81 - 7.93 (m, 2 H)₃ 7.13 - 7.23 (m, 2 H), 6.94 (s, 1 H), 6.76 (t, J=6.78 Hz, 1 H), 5.95 (d, J=4.52 Hz, 1 H), 4.04 (s, 3 H), 2.98 (d, J=5.02 Hz, 3 H), 2.33 (s, 3 H)₅ 1.61 - 1.72 (m, 1 H), 1.02 (d, ./=6.78 Hz, 6 H), 0.84 - 0.96 (m, 2 H), 0.73 - 0.84 (m, 2 H). LCMS retention time: 2.502 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of t min, and an analysis time of 4 min where solvent A was 10% CH₃ OH / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 533 (MH¹).

4~fluoro-2-(4-fluorophenyl)-5-(5-(l-(3-fluorophenyl)cycIopropylcarbatnoyl)-4- methoxy-2-methylpheny l)-N-methylpyrazolo [ 1 ,5-a] py ridin e-3-carboxamide . To a solution containing l-(3-fiuorophenyl)cyclopropanamine hydrochloride (0.022 g, 0.12 mraol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro-2-(4- fluoroρhenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B = 10% H₂CYCH₃OH)/ A (A - 90% H₂O/ CH₃OH), 12 rain, gradient, analysis time 15 min.) afforded 4-fluoro-2-(4-fluoroρhenyl)-5-(5-(l-(3- fluorophenyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)~N" methy]ρyrazolo[l₅5-a]ρyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 12.0 min. IH NMR (400 MHz₅ CHLOROFORM-^) δ ppm 8.46 (s, 1 H), 8,34 (d, /=7.03 Hz, 1 H), 8.11 (s, 1 H), 7.80 - 7.89 (m, 2 H), 7.22 - 7.27 (m, 1 H), 7.13 - 7.21 (m, 2 H), 6.96 - 7.06 (m, 3 H), 6.84 - 6.92 (m, 1 H), 6.75 (t, /=6.78 Hz, 1 H), 5.92 (d, J=4.02 Hz, 1 H), 4.08 (s, 3 H), 2.97 (d, J=5.02 Hz, 3 H), 2.34 (s, 3 H), 1.36 - 1.45 (m, 4 H). LCMS retention time: 2.480 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3,0 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 iiM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 585 (MH⁺).

4-fluoro-2-(4-fluorophenyl)-5-(5-(l-(2-fluorophenyl)cyclopropylcarbamoyl)-4- methoxy-2-methylphenyl)-N-methylpyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing l-(2-fiuorophenyl)cyclopropanamine hydrochloride (0.022 g, 0.12 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol)_} 5-(4-fluoro-2-(4- fluoroρhenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 5O x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 0-100% B (B = 10% H₂O/CH₃OH)/ A (A = 90% H₂O/ CH₃OH), 12 min. gradient, analysis time 15 min.) afforded 4-fiuoro-2-(4-fluorophenyl)-5-(5-(l-(2- fiuorophenyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N- methylpyrazolo[l,5-a3pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 12-.3 min. IH NMR (400 MHz, CHLOROFORM-*/) δ ppm 8.63 (s, 1 H), 8.32 (d, J=7.03 Hz, 1 H), 8.05 (s, 1 H), 7.79 - 7.89 (m, 2 H), 7.67 (td, J=7.65, 1.76 Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.10 (td, 7=7.53, 1.25 Hz, 1 H), 7.02 (ddd, JH0.67, 8.16, 1.00 Hz, 1 H), 6,91 (s, 1 H), 6.70 (t, /=6.78 Hz, 1 H), 5.87 (br. s., 1 H), 4.05 (s₅ 3 H), 2.96 (d, J-5.02 Hz, 3 H), 2.30 (s, 3 H), 1.29 (s, 4 H). LCMS retention time: 2.553 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 220 nM.

The elation conditions employed a flow rate of 4 mL/inin, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 585 (MH⁺).

4-fluoro-2-(4-fluorophenyi)-5-(4-methoxy~2-methyl-5-(l-(pyriinidin-2- y^cyclopropylcarbamoyOphenyty-N-methylpyrazolo^S-ajpyridine-S- carboxamide. To a solution containing l-(pyrimidin-2-yl)cyclopropanamine (0.021 g, 0.089 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro-2-(4- fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5-a]pyridm-5-yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 0-100% B (B = 10% H₂O/CH₃OH)/ A (A = 90% H₂O/ CH₃OH), 12 min. gradient, analysis time 15 min.) afforded 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy- 2-methyl-5-(l-φyrimidin-2-yl)cycloproρylcarbamoyl)phenyl)-N- methylpyrazoIo[l,5-a]ρyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 10.3 min. IH NMR (500 MHz, MeOD) δ ppm 8.70 (d, ./=4.88 Hz, 2 H), 8.54 (d, J=7.02 Hz₅ 1 H), 7.96 (s, 1 H), 7.86 - 7.94 (m, 2 H)₅ 7.21 - 7.31 (m, 4 H), 6.92 (t, J-6.87 Hz, 1 H)₁ 4.85 - 4.95 (m, 14 H)₅ 4.10 (s, 3 H)₅ 3.28 - 3.38 (m, 21 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 1.78 - 1.88 (m, 2 H), 1.50 - 1.59 (m, 2 H). LCMS retention time: 2.138 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 niM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 569 (MH⁺).

4-fluoro-2-(4-fluorophenyl)-N-methyI~5-(2~methyl-5-(l-(pyrimidin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazαlo[l,5-a]pyridine-3-carboxamide. To a solution containing l-(pyrimidin-2-yl)cyclopropanamine (0.030 g, 0.18 mmol), diisopropylethylamine (0.16 niL, 0.95 mmol), 3-(4~fluoro-2-(4-fluorophenyl)-3- (methylcarbamoylJpyrazolotl_jS-aJpyridin-S-y^^-methylbenzoic acid (0.050 g, 0.12 mmol) and DMF (0.8 niL) was added HATU (0.09 g, 0.24 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 10-100% B (B = 10% H₂O/CH₃OH)/ A (A = 90% H₂O/ CH₃OH), 12 min. gradient) to afford 4~fluoro-2-(4-fluorophenyl)-N- methyl-5-(2-methyl-5-(l~(pyrimidin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 10.1 min. IH NMR (400 MHz, CHLOROFORM-J) δ ppm 8.77 (d, J=5.02 Hz, 2 H), 8.40 (d, /=7.03 Hz, 1 H), 7.76 - 7.87 (m, 3 H)₃ 7.73 (s, 1 H), 7.43 (d, J=7.78 Hz₅ 1 H), 7.29 - 7.36 (m, 2 H), 7.12 - 7.23 (m, 2 H), 6.79 (t, J=6.78 Hz, 1 H), 5.97 (br. s., 1 H), 2.99 (d, ./=5.02 Hz, 3 H), 2.34 (s, 3 H), 1.92 - 2.00 (m, 2 H)₅ 1.60 - 1.70 (m, 2 H). LCMS retention time: 2.000 min. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 539 (MH⁺).

ter t-b uty 15,7-dichIo ro~2~(4-fluo rophenyl)py r azolo [ 1,5-a] py ridiiie-3- carbonyl(methyl)carbamate. To a cooled solution (0° C, ice bath) containing 2,4- dichloropyridine (4.0 g, 27.0 mmol) and dichlorome thane (60 mL) was added O- (mesitylsulfonyl)hydroxylamme (10.2 g, 27.0 mmol) in dichloromethane (75 mL) quickly, dropwise. The solution was maintained at 0° C for 15 min, removed from the cooling bath and maintained at ambient temperature for 20 h. The solution was concentrated to afford l-amino-2,4-dichloropyridinium 2,4,6- trimethylbenzenesulfonate as a light yellow foam ( 165 MH⁺). The product thus obtained was combined with tert-butyl 3-(4~ fluorophenyl)propioloyl(methyl)carbamate (6.6 g, 24.0 mmol) and THF (100 mL). The resultant solution was cooled to - 78° C (dry ice, acetone bath) and DBU (7.2 mL, 48.0 mmol) was added dropwise over 10 min with rapid stirring. The mixture was kept in the cooling bath with stirring and allowed to proceed for 15 h at ambient temperature. The mixture was then filtered and concentrated. Purification on silica gel (0-80% ethyl acetate/hexanes, 60 min gradient) afforded an off white residue. The residue thus obtained was further purified using preparative HPLC (Phenomonex-Luna, 50 x 100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B = 10% H₂OZCH₃OH)/ A (A - 90% H₂O/ CH₃OH), 15 min. gradient) to afford tert- butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[ 1 ,5-a]pyridine-3- carbonyl(methyl)carbamate as a white solid. Preparative HPLC retention time: 14,0 min. IH NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.81 (d, /=2.26 Hz, 1 H)₅ 7.71 (dd, /=8.91, 5.40 Hz, 2 H), 7.16 (t, /=8.66 Hz, 2 H), 7.03 (d, /=2.26 Hz, 1 H), 3.26 (s, 3 H), 1.12 (s, 9 H). LCMS retention time: 2.810 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 460 (MNa⁺).

Tert-butyl 5-chloro-7-fluoro-2-(4~fluorophenyl)pyrazolo[l,5-a]pyridine-3- carbonyl(methyl)carbamate. To a solution containing tetrabutylammoniumcyanide and THF (0.912 mL, 1.0 M) was added a solution containing hexafluorobenzene and THF (0.760 mL, 0.2 M) at -35°C (caution, exothermic). The solution was removed from cooling and maintained at ambient temperature for 150 min. The solution thus obtained was cooled to 0⁰C (ice bath) and added dropwise with stirring to a pre- cooled solution (-5O⁰C, dry ice, acetone) containing tert-butyl 5,7-dichloro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridine-3-carbonyl (methyl) carbamate and THF (0.608 mL, 0.38 M). The solution thus obtained was removed from cooling and allowed to proceed for 18h. The solution was poured into water (25 mL). The aqueous portion was then extracted with ethyl acetate (2 x 25 mL). The organic portions were combined, then washed with water (3 x 20 mL), then washed with brine (25 mL), then dried over MgSO₄, filtered and concentrated. The residue thus obtained was purified on silica gel (0-20% ethyl acetate/hexanes, 25 min gradient) to afford tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridine-3- carbonyl(methyl)carbamate as a white solid. 1 H NMR (400 MHz, CHLOROFORM- d) δ ppm 7.65 - 7.76 (m, 3 H), 7.11 - 7.20 (m, 2 H), 6.64 (dd, /=4.77, 2.01 Hz, 1 H), 3.27 (s, 3 H), 1.12 (s, 9 H). LCMS retention time: 2.743 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 roM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 422 (MH⁺).

3-(3-(tert-butoxycarbonyl(methyI)carbamoyl)-7-fluoro-2-(4- fluorophenyI)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid. To a degassed mixture containing tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[l,5- a]pyridine-3-carbonyl(methyl)carbamate (0.060 g, 0.14 mmol), 4-methyl-3-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoic acid (0.047 g, 0.18 mmol), sodium carbonate (0.043 g, 0.43 mmol), dioxane (1.2 mL) and water (0.24 niL) was added tetrakis(tiphenylphosphine)palladium(0) (0.005 g, 0.004 mmol). The mixture was stirred at 95°C for 18 h. The mixture was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2 x 15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fiuoro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.725 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 522 (MH⁺).

Tert-butyl 7-fluoro-2-(4-fluorophenyl)~5-(2-methyl-5-(l-phenylcyclopropyl carbamoy^phenyOpyrazolotl^-alpyridine-S-carbonyltmethylJcarbaraate. To a solution containing l-phenylcyclopropanamine hydrochloride (0.010 g, 0.061 mmol), diisopropylethylamine (0,086 mL, 0.49 mmol), 3-(3-(tert- butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[l,5- a]pyridin-5-yl)-4-methylbenzoic acid (0.032 g_> 0.061 mmol) and DMF (0.41 mL) was added HATU (0.047 g, 0.12 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7- fluoro-2-(4-fluorophenyl)-5-(2-rnethyϊ-5-(l- phenylcyclopropylcarbamoyl)phenyl)pyrazolo [1,5 -a]pyridine-3 - carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.938 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 637 (MH⁺).

7-fluoro-2-(4-fluorophenyl)-N-methyl-S-(2-methyI-5-(l- phenylcyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(l- phenylcyclopropyl carbamoyl)phenyl)pyrazolo [1,5 -a]pyridine- 3 -carbonyl(methyl) carbamate (0.035 g, 0.053 mmol) and dichloromethane (4.0 mL) was added TFA (0.33 mL, 4,3 mmol) at room temperature. The solution was maintained for 15 min at room temperature and concentrated to dryness. The residue thus obtained was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1M ammonium acetate, 10-100% B (B = 5% H₂O/CH₃CN)/ A (A = 95% H₂O/ CH₃CN), 15 min. gradient) to afford 7-fluoro-2-(4-fluorophenyl)-N-methyl-5- (2-methyl-5-(l-phenyicyclopropylcarbamoyl)phenyl) pyrazolo[l_s5-a]pyridine-3- carboxamide as a white solid. Preparative HPLC retention time: 11.0 min. IH NMR (400 MHz, CHLOROFORM-0 δ ppm 8.15 (d, J=LSl Hz, 1 H), 7.70 - 7.83 (m, 4 H), 7.39 (d, J=8.03 Hz, 1 H), 7.23 - 7.36 (m, 7 H), 6.91 (s_> 1 H), 6.66 (dd, J=5.52, 1.51 Hz, 1 H)₅ 5.57 (d, J=4.27 Hz, 1 H)₅ 2.87 (d, 7=5.02 Hz, 3 H), 2.40 (s, 3 H), 1.35 - 1.47 (m, 4 H). LCMS retention time: 2.510 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromato graph equipped with a Phenoroenex-Luna, 10 micron, C18, 3.0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 537 (MH^H).

tert-butyl 7-fluoro-2~(4~fluorophenyl)-5-(2-methyl-5-(l-(pyridin-2- ytycyclopropylcarbamoytyphenyOpyrazolotl^-alpyridine-θ- carbonyl(methyl)carbamate. To a solution containing l-(pyridin-2- yl)cyclopropanamine dihydrochloride (0.011 g, 0.054 mmol), diisopropylethylamine (0.075 ml, 0.43 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4- fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.054 mmol) and DMF (0.36 mL) was added HATU (0.041 g, 0.11 mmol) in one portion, The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(l-(ρyridin- 2-yl)cyclopropylcarbamoyl)phenyl)ρyrazolo [ 1 , 5 -a] pyridine-3 - carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.428 min. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a

Phenomenex-Luna, 10 micron, Cl 8, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min., a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA, MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 638 (MH⁴).

7-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide. To a solution containing tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(l-(pyridin- 2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[ 1 ,5-a3pyridine-3- carbonyl(methyl) carbamate (0.022 g, 0,035 mmol) and dichloromethane (3.0 niL) was added TFA (0,22 mL, 2.8 mmol) at room temperature. The solution was maintained for 15 min at room temperature and concentrated to dryness. The residue thus obtained was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, C18 column; OJM ammonium acetate, 10-100% B (B - 5% H₂CVCH₃CN)/ A (A - 95% H₂O/ CH₃CN), 15 min. gradient) to afford 7-fluoro-2-(4-fluorophenyl)- N-methyl-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide as a white solid. Preparative HPLC retention time: 9.0 min. IH NMR (400 MHz, CHLOROFORMS δ ppm 8.44 - 8.54 (m, 1 H), 8.18 (d, J=I .51 Hz₅ 1 H), 7.79 - 7.85 (m, 2 H), 7.72 - 7.78 (m, 2 H), 7.61 (td, J=7.78, 1.76 Hz, 1 H), 7.41 (dd, J=8.03, 3.26 Hz, 2 H), 7.22 - 7.32 (m, 2 H), 7.20 (s, 1 H), 7.08 (ddd, J-7.40, 4.89, 1.25 Hz, 1 H), 6,69 (dd, /=5.65, 1.63 Hz, 1 H), 5.58 (d, J-4.52 Hz, 1 H), 2.87 (d, J=5.02 Hz, 3 H), 2.42 (s, 3 H), 1.67 - 1.78 (m, 2 H), 1.39 - 1.48 (m, 2 H). LCMS retention time: 1.873 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3,0 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 rnL/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH₃ OH / 90% H₂O / 10 mM TFA and solvent B was 10% H₂O / 90% CH₃OH / 10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode, m/z 538 (MH⁺).

5-bromo-2-(4-fluorophenyl)furo[2,3-blpyridine. 5-bromo-3-iodopyridm-2-ol (6.7 g, 22 mmol) (Heterocycles. 57, 1, pp 55), l-ethynyl-4-fluorobenzene (4.03 g, 33.5 mmol), copper(I) iodide (0.255 g, 1.34 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (0.784 g, 1.12 mmol) were combined and evacuated/backfilled with N2 (3x) then diluted with triethylamine (223 mL) and heated to 90 ⁰C for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL), brine, dried over Na2SO4, filtered, and concentrated. Trituration with Et20 afforded the expected product 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridme (4,2 g, 14.4 mmol, 64 % yield). IH NMR (400 MHz, DMSO-d«) δ ppm 8.35 - 8.42 (2 H, m), 8.03 (2 H, dd, J=8.78, 5.27 Hz), 7.46 (1 H, s), 7.39 (2 H, t, J-8.91 Hz). LC-MS retention time: 2.36 min; m/z (MH+): 292, 294. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

3-(2~(4-fluorophenyl)fuπ>[2,3-b]pyridin-5-yl)benzoic acid. 3- Carboxyphenylboronic acid (700 mg, 4,22 mmol), 5-bromo-2-(4- fluorophenyl)furo[2_>3-b]pyridine (750 mg, 2,57 mmol), Pd(Ph3P)4 (30 mg, 0.026 mmol), and Cs2CO3 (1.25g, 3.84 mmol) were combined in dioxane (20 mL) and water (4 mL). The mixture was evacuated/backfilled with nitrogen (3x). The reaction was heated to 95 ⁰C under N2 (g) overnight. The mixture was partitioned between EtOAc and 1 N HCl. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a brown solid which was triturated with Et2O to give the expected product 3-(2-(4-fluorophenyl)furo[2,3- b]pyridin-5~yl)benzoic acid (255 mg, 30% yield) consistent by LCMS. LC-MS retention time: 1.83 min; m/z (MH+): 334. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0x5 Omm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1 % trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid. NBS (125 mg, 0.702 mmol) was added to a stirred suspension of 3-(2-(4~fluorophenyl)furo[2,3- b]pyridin-5-yl)benzoic acid (215 mg, 0.645 mmol) in THF (5 mL)/DMF (1 niL). The solids dissolved and the reaction was stirred at room temperature for 30 min, then quenched with 10% Na2S2O3, and acidified with 1 N HCl. The solvent was evaporated and the material was diluted with water, filtered and dried to afford a mixture of starting material and product. The material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S2O3, and the solution was acidified with 0.1 N HCl. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et2O, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53% yield) as an off-white powder consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d^) δ ppm 8.73 (1 H, d, J=2.26 Hz), 8.27 - 8.33 (2 H, m), 8.19 - 8.26 (2 H, m), 8.05 - 8.12 (1 H, m), 8.03 (1 H, d, J-7.78 Hz), 7.68 (1 H, t, J=7.78 Hz), 7.45 - 7.55 (2 H, m). LC-MS retention time: 1.20 min; m/z (MH+): 412, 414. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B₁ a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

S-bromo-2-(4-fluorophenyI)-N-raethylfuro[3,2-b]pyridine-3-carboxamide. Step 1: Preparation of 6-bromo-2-iodopyridin-3-ol. N-iodosuccinimide (6.47 g, 28.7 mmol) was added to a stirring solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in MeOH (144 mL) at 45 ⁰C. It was allowed to stir for 3 hours. The mixture was concentrated and triturated with Et20. The precipitate was discarded and the filtrate was concentrated and triturated with dichloromethane to give the expected product, 1 6-bromo-2-iodopyridin-3-ol (3150 mg, 10.50 mmol, 37 % yield) by LCMS and NMR. IH NMR (400 MHz, DMSOdβ) δ ppm 11.12 (1 H, s), 7.42 (1 H, d, J=8.28 Hz)₅ 7.10 (1 H, d, J=8.28 Hz). LC-MS retention time: 1.27 min; m/z (MH+): 300, 302. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 2: Preparation of 6-bromo-2-iodopyridin~3-yl acetate. 6-bromo-2-iodopyridin- 3-ol (150 mg, 0.500 mmol) was added to acetic anhydride (2.4 mL, 25 mmol) at 130 ⁰C. It was allowed to stir for 30 min then concentrated and chased with toluene to give the expected product 6-bromo-2-iodopyridm-3-yl acetate (171 mg, 0.500 mmol, 100 % yield) by NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 7.74 (1 H, d, J=8.28 Hz), 7.62 (1 H, d, J-8.28 Hz), 2.36 (3 H, s). LC-MS retention time: 1.66 min; m/z (MH+): 342, 344. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4, 6x5 Omm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM.. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0,1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of 6-bromo-2-((4-fluoroρhenyl)ethynyl)pyridin-3-yl acetate. 6- bromo-2-iodopyridin-3-yl acetate (3.50 g, 10.24 mmol)_s l-ethynyl-4-fluorobenzene (1.11 g, 9.21 mmol), copper (I) iodide (117 mg, 0.614 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (359 mg, 0.512 mmol) were combined and evacuated/backfilled withN2 (3x) then diluted with triethylamine (100 ml) and heated to 85 ⁰C for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL) and brine, dried over Na2SO4_s filtered, and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 6-bromo-2-((4-fluorophenyl)ethynyl)pyridm-3-yl acetate (2.26 g, 6.76 mmol, 66.1 % yield) consistent by NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 7.77 (2 H, s), 7.70 (2 H, dd, J=8.78₅ 5.52 Hz)₃ 7.34 (2 H, t, J=8.91 Hz), 2.41 (3 H, s). LC-MS retention time: 2.18 min; m/z: parent ion not observed, -Ac: 292, 294. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H20 / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of methyl 5-bromo-2-(4-fluorophenyl)furo[3,2-b]ρyridine-3- carboxylate. Sodium acetate (15 mg, 0.18 mmol), K2CO3 (25 mg, 0.18 mmol), copper(II) chloride dihydrate (46 mg, 0.27 mmol), palladium(II) chloride (2.0 mg, 0.012 mmol) was added to a stirring solution of 6-bromo-2-((4- fluorophenyl)ethynyl)pyridm-3-yl acetate (30 mg, 0.090 mmol) in MeOH (2 mL) at room temperature in a Parr Bomb. The vessel was charged with 300 PSI of CO (g) and allowed to stir at room temperature overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product methyl 5-bromo-2-(4-fluorαphenyl)furo[3,2-b]pyridme-3-carboxylate (25 mg, 0.071 mmol, 80 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) d ppm 8.16 (1 H, d, J=8.78 Hz), 8.04 (2 H, dd, J=8.91, 5.40 Hz), 7.67 (1 H, d, J-8.78 Hz), 7.44 (2 H, t, J=8.78 Hz), 3.89 (3 H, s). LC-MS retention time: 2.05 min; m/z (MH+) :350. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 84.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of 5-bromo-2-(4-fluorophenyl)-N-methylfuro[3,2-b]pyridine-3- carboxamide. NaOH (5 niL, 5.00 mmol, IM aq) was added to a stirring solution of methyl 5-bromo-2-(4-fluorophenyl)fuiO[3,2-b]pyridine-3-carboxylate (350 mg, 1.00 mmol) in THF (5 mL) and MeOH (5 mL) at 60 ⁰C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 5-bromo-2- (4-fluorophenyl)furo[3,2-b]pyridine-3-carboxylic. The crude residue was diluted with DMF (10 mL) and treated with HATU (456 mg, 1.20 mmol), methanamme (2.5 mL, 5.00 mmol, 2.0 M in THF)₅ followed by DIEA (524 μL_? 3.00 mmol). It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product (250 mg_? 68% yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-dό) δ ppm 8.57 (1 H, br. s.), 8.10 - 8.18 (3 H, m), 7.67 (1 H, d, J-8.53 Hz), 7.42 (2 H, t, J=8.78 Hz), 2.90 (3 H₉ d, J=4.52 Hz). LC-MS retention time: 2.03 min; m/z (MH+): 349, 351. LC data was recorded on a Shimadzu LC-IOAS liquid cbxomatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

2-(4-fluorophenyI)-3-(methylcarbamoyl)furo[2,3-c]pyridin-5-yl tπfluoromethanesulfønate. Step 1: Preparation of 2-(benzyloxy)-5- (methoxymethoxy) pyridine. NaH (1.2 g, 29.8 mmol) was added to a stirring solution of 6-(benzyloxy) pyridin-3-ol (5.0 g, 24.85 mmol) in DMF (100 mL) at 0⁰C. Then it was allowed to warm to room temperature and stir for 25 min then was treated with MOM-Cl (2.55 mL, 28.6 mmol) and the reaction was allowed to stir for 2 hrs. The mixture was quenched with H2O then concentrated about 80% then diluted with EtOAc and washed with H2O, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 2-(benzyloxy)-5-(methoxymethoxy) pyridine (5.41 g, 22.1 mmol, 89 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, CHLOROFORM-d) 6 ppm 7.97 (1 H, d, J=3.01 Hz), 7.42 - 7.49 (2 H, m), 7.29 - 7.41 (4 H, m), 6.76 (1 H, d, J=9.03 Hz), 5.34 (2 H, s), 5.12 (2 H, s), 3.50 (3 H, s). LC-MS retention time: 1.88 min; m/z (MH+): 246. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-I OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetom^'trile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 2: Preparation of 2-(benzyloxy)-4-iodo-5-(methoxymethoxy) pyridine. tBuLi (27 mL, 46.2 mmol) was added drop wise to a stirring solution of 2-(benzyloxy)-5- (methoxymethoxy)pyridine (5.4 g, 22.06 mmol) in THF (110 mL) at -78 ⁰C. The light yellow solution was allowed to stir for 30 min then treated with a solution of iodine (8.4 g, 33.1 mmol) in THF (55 mL) dropwise (the purple color per drop dissipated until after 1.05 equiv was added, then it turned progressively purple). It was allowed to stir for 1 hour and then quenched with H2O and diluted with EtOAc washed with sodium thiosulfate sat. soln and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.90 g, 10.5 mmol, 48 % yield) by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1 H₅ s), 7.28 - 7.44 (6 H, m), 5.28 (2 H, s), 5.21 (2 H, s), 3.43 (3 H, s). LC-MS retention time: 2.36 min; m/z (MH+): 372. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of 2- (benzyloxy)-4-((4-fluorophenyl)ethynyl}-5- (methoxymethoxy)pyridine. 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (3.0 g, 8.08 mmol), copper (I) iodide (92 mg, 0.485 mrnol), PdC12(PPh3)2 (284 mg, 0.404 mmol), 1 -ethynyl-4-fluorobenzene (1.07 g, 8.89 mmol) were combined in dioxane (40 mL) and TEA (40 mL), degassed and stirred at 80 ⁰C for 1.5 hrs. The mixture was diluted with EtOAc and washed with sat NaCl and H2O. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 ran) to give the expected product 2-(benzyloxy)-4-((4-fluorophenyl)ethynyl)-5-(methoxymethoxy)ρyridine (2.52 g, 6.93 mmol, 86 % yield) consistent by LCMS. LC-MS retention time: 2.71 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of 6-(benzyloxy)-4-((4-fluorophenyl)ethynyl)pyridin-3-ol. Trifluoroacetic acid (0.95 mL, 12.4 mmol) was added to a stirring solution of 2-

(benzyloxy)~4-((4~fluorophenyl)ethynyl)-5-(methoxymethoxy)pyridine (450 mg, 1.24 mmol) in dichloroethane (5 mL) at room temperature. It was allowed to stir for 5 hours and then concentrated to dryness to give 6-(benzyloxy)-4-((4- fluoroρhenyl)ethynyl)pyridin-3-ol (395 mg, 1.24 mmol, 100 % yield) consistent by LCMS. LC-MS retention time: 2.49 min; m/z (MH+): 320. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u CIS 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B₃ a gradient time of 3 min, a hold time of 1 mitt, and an. analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of methyl 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine- 3-carboxylate. Sodium acetate (1.14 g, 13.9 mmol), K2CO3 (1.92 g, 13.9 mmol), copper (II) chloride dihydrate (3.56 g, 20.9 mmol), palladium (II) chloride (0.205 g, 1.15 mmol) was added to a stirring solution of 6-(benzyloxy)-4-((4- fluorophenyl)ethynyl)pyridin-3-ol (2.22 g, 6.95 mmol) in MeOH (150 mL) at room temperature in a Parr Bomb. The vessel was charged with 300 PSI of CO (g) and allowed to stir at room temperature overnight. The mixture was concentrated then diluted with EtOAc and washed with H2O, and sat NaCl. The organic phase was dried over Na2SO4_> filtered and concentrated to give the expected product methyl 5- (benzyloxy)-2-(4-fluorophenyl)furo[2_?3-c]pyridme-3-carboxylate (2.62 g, 6.95 mmol, 100 % yield) by LCMS. LC-MS retention time: 2.66 min; m/z (MH+): 378. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 6: Preparation of 5~(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3- carboxylic acid. NaOH (27.8 mL, 27.8 mmol, IM aq.) was added to a stirring solution of methyl 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3- carboxylate (2.62 g, 6.94 mmol) in THF (174 mL) and MeOH (174 mL) at 60 ⁰C for 2 hours. The mixture was diluted with ethyl acetate and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(benzyloxy)-2-(4-fluorophenyl)furo[2,3-c]pyridine-3- carboxylic acid (2.52 g, 6.94 mmol, 100 % yield) consistent by LCMS. LC-MS retention time: 2.19 min; m/z (MH+): 364. LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x5 Omni column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 7: Preparation of 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2_>3- c]pyridine-3-carboxamide. Methanamine (3.1 mL, 6.2 mmol, 2M in THF) was added to a stirring solution of DIEA (646 μL, 3.70 mmol), HATU (563 mg, 1.48 mmol), 5- (berjzyloxy)-2-(4-fluoroρhenyl)furo[2₅3-c]pyridine-3-carboxylic acid (448 mg, 1.23 mmol) in DMF (12 mL) at room temperature, The mixture concentrated then diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give 5-(benzyloxy)-2-(4-fluorophenyl)- N-methylfuro[2_J3-c]pyridine-3-carboxamide (180 mg, 39% yield) consistent by

LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1 H, s), 8.37 - 8.45 (1 H, m), 7.98 - 8.08 (2 H, m), 7.29 - 7.50 (7 H, m), 7.06 (1 H, s), 5.42 (2 H, s), 2.83 (3 H, d, J=4.52 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 377. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-I OAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B₅ a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 8: Preparation of 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2,3-c]pyridine-3- carboxamide. Pd/C (178 mg, 0,084 mmol) (10%; 50% wet) was added to a stirring solution of 5-(benzyloxy)-2-(4-fluorophenyl)-N-methylfuro[2,3-c]pyridine-3- carboxamide (630 mg_> 1.674 mmol) in THF (83 ml) at room temperature. It was placed under an atmosphere of H2 and allowed to stir for 20 minutes after which a precipitate had formed. The reaction was purged with N2 and diluted with MeOH until all solids had dissolved. The mixture was filtered through a pad of celite washing with MeOH and the filtrate was concentrated to give the expected product 2-(4-fluorophenyl)-5-hydroxy-N-methylfuro[2_f3-c]pyridine-3-carboxamide (460 mg, 1.53 mmol, 91 % yield) consistent by LCMS and NMR. 1 H NMR (400 MHz,

DMSO-d6) 6 ppm 8.30 - 8.40 (2 H, m), 7.98 (2 H, dd, J-8,78, 5.77 Hz), 7.35 - 7.45 (3 H, m), 6.61 (1 H₅ s), 2.81 (3 H, d, J=4.52 Hz). LC-MS retention time: 0.847 min; m/z (MH+): 287. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/mm, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 9: 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-c]pyridin-5-yl trifluoromethanesulfonate. Triflic anhydride (TGO, 319 μL, 1.89 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-5-hydroxy~N-methylfuro[2,3-c]pyridine- 3-carboxamide (270 mg, 0.943 mmol) in pyridine (13 mL) at O⁰C and the mixture was allowed to warm to room temperature. It was allowed to stir for 1 hour then concentrated and diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3- c]pyridin-5-yl trifluoromethanesulfonate (188 mg, 0.449 mmol, 34.8 % yield)consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1 H, s), 8.53 - 8.61 (1 H, m), 8.01 - 8.11 (2 H₅ m), 7,87 (1 H, s), 7.46 (2 H, t, J=S.91 Hz), 2.85 (3 H, d, J-4.52 Hz). LC-MS retention time: 2.06 min; m/z (MH+): 419. LC data was recorded on a Shimadzυ LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

2-(4~fIuorophenyl)-N-methyl-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyI)furo[2,3-b]pyridine-3-carboxamide. Step 1 : Preparation of

3-(3-bromo-2-(4-fluorophen.yl)furo[2_s3-b]pyridin-5-yl)-N-(2-phenylpropan-2- yl)benzamide. DIEA (210 μL, 1.20 mmol) was added to a stirring solution of HATU (228 mg, 0.600 mmol), 2-phenylpropan-2-amine (69.1 μL, 0.480 mmol), 3-(3-bromo- 2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (165 mg, 0,400 mmol) in DMF (4 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et20 to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3~b]pyridin-5-yl)-N-(2- phenylpropan-2-yl)benzamide (180 mg, 0.340 mmol, 85 % yield) consistent by

LCMS and NMR. IH NMR (500 MHz, DMSO-d₆) δ ppm 8.78 - 8.86 (1 H, m), 8.60 (1 H_s s), 8.34 - 8.38 (1 H, m), 8.27 (1 H, s), 8.19 - 8.26 (2 H, m), 7.99 (1 H, d, J=7.93 Hz), 7.89 (1 H, d, J-7.93 Hz), 7.61 (1 H, t, J=7.63 Hz), 7.46 - 7.55 (2 H, m), 7.42 (2 H, d, J-7.32 Hz), 7.30 (2 H, t, J=7.78 Hz), 7.18 (1 H_} t, J=7.17 Hz), 1.72 (6 H, s). LC-MS retention time: 1.97 min; m/z (MH+): 529, 531. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou CIS 3.0x50mm column using a SPD-IOAV XJV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 raM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode,

Step 2: Preparation of 3-(2-(4-fiuorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2- phenylpropan-2-yl)benzamide. Pd(Ph3P)4 (4.4 mg, 3.8 μmol) was added to a stirring solution of 3 -(3 -bromo-2-(4-fiuorophenyl)furo [2,3 -b]pyridin- 5 -yl)-N-(2 - ρhenylρroρan-2-yl)benzamide (20 mg, 0.038 mmol), trimethylboroxine (11 μL, 0.076 mmol), and Na2CO3 (12.0 mg, 0.11 mmol) in DMF (1.4 mL) and Water (.14 mL) at room temperature. It was subjected to microwave irradiation: 180 ⁰C for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO 3, and sat NaCl, The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N- (2-phenylpropan-2-yl)benzamide (15 mg, 0.032 mmol, 85 % yield) by LCMS. LC- MS retention time: 1.87 min; m/z (MH+): 465. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 22OnM.

The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 3: Preparation of 3-(2-(4-fluorophenyl)-3-formylfixro[2,3-b]pyridin-5-yl)-N-(2- phenyϊρropan-2-yl)benzamide. AIBN (1.0 mg, 6.1 μmol) was added to a stirring solution of NBS (4.6 mg, 0.026 mrnol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3- b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (11 mg, 0.024 mmol) in CC14 (1 niL). The mixture was heated to 76 ⁰C and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (3.4 mg, 0.028 mmol) and subjected to microwave irradiation (150⁰C) for 5 min. The reaction was purified by preparative reverse phase HPLC on a Cl 8 column using a suitably buffered H₂O/CH₃CN gradient, and concentrated to give to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2- yl)benzamide (7.5 mg, 0.016 mmol, 66 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, DMSO-d₆) δppm 10.31 (1 H, s), 8.84 (1 H, s), 8.79 (1 H, s), 8.65 (1 H, s), 8.19 - 8.26 (3 H₉ m), 7.89 - 7.97 (2 H, m), 7.59 - 7.67 (1 H, m), 7.54 (2 H, t, J=8.55 Hz), 7.42 (2 H, d, J=7.93 Hz), 7.30 (2 H₅ 1, J-7.63 Hz), 7.13 - 7,23 (1 H, m), 1.71 (6 H, s). LC-MS retention time: 1.75 min; m/z (MH+): 479. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 84.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitriie / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitriie / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid. Oxone (28 mg, 0.046 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-formylfuro[2_>3- b]ρyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.042 mmol) in DMF (.5 mL) at room temperature. It was allowed to stir for 3 days. An additional amount of Oxone (28 mg, 0.046 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (7 mg, 0.014 mmol, 34 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, MeOD) δ ppm 7.42 (1 H, d, J=2.14 Hz), 7.31 - 7.39 (2 H, m), 6.93 - 7.02 (2 H, m), 6.87 (1 H, s), 6.59 (2 H, t, J-8.70 Hz), 6.34 (1 H_s t, J-7.63 Hz), 6.20 (2 H, d, J-7.63 Hz), 5.97 - 6.07 (4 H, m), 5.92 (1 H, t, J=I 32 Hz), 0.52 (6 H₅ s). LC-MS retention time: 1.15 min; m/z (MH+): 495. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of the title compound, 2-(4-fluorophenyl)-N-methyl-5-(3-(2- phenylproρan-2-ylcarbamoyl)ρhenyl) furo [2 , 3 -b] pyridine-3 -carboxamide. Methanamine (253 μL, 0.506 mmol, 2M in THF) was added to a stirring solution of 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine- 3-carboxylic acid (50 mg, 0.10 mmol), DIEA (53 μL, 0.30 mmol), DMAP (1.2 mg, 10 μmol), HATU (58 mg, 0.15 mmol) in DMF (1 mL) at room temperature. It was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a Cl 8 column using a suitably buffered H₂O/CH₃CN gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2- ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (7 mg, 0.013 mmol, 13 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, MeOD) 5 ppm 8.65 (1 H, d, J=2.14 Hz), 8.41 (1 H, d, J=2.14 Hz), 8.12 - 8.17 (1 H, m), 8.00 - 8.06 (2 H, m), 7.84 - 7.92 (2 H, m), 7.62 (1 H, t, J=7.63 Hz), 7.43 - 7.50 (2 H, m), 7.26 - 7.35 (4 H, m), 7.19 (1 H, t, J=7.32 Hz), 2.98 (3 H, s), 1.78 (6 H, s). LC-MS retention time: 1.77 min; m/z (MH+): 508. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-I OAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H20 / 90% MeOH / 0.1% trifluoroacetic acid, MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% CH₃CN/95% H₂O/0.1% TFA, Solvent B - 95% CH₃CN/5% H₂O/0.1% TFA, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/mitt. Column: Waters Sunfire C-18, 4.6 x 150 mm, 3.5 mm, R₁ = 12.82 min, purity = 95%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, R₁ = 11.20 min, purity = 94%. Additional HPLC method: Solvent A = 5% MeOH/95% H₂OAO mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/IO mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C-18, 4.6 x 150 mm, 3 mm, Rt = 14.10 min, purity = 95%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, R_t = 13.85 min, purity = 95%.

2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyOpheny^furoIljS-blpyridine-S-carboxaniide. Step 1 Preparation of 3-(3-broiτio-2-(4-fluorophenyl)furo[2,3~b]pyridin-5-yl)-N-(l - phenylcyclopropyl)benzamide. DIEA (286 μL, 1.64 mmol) was added to a stirring solution of HATU (311 mg, 0.819 mmol), 1-phenylcycloproρanamine hydrochloride (111 mg, 0.655 mmol), and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5- yljbenzoic acid (225 mg, 0.546 mmol) in DMF (6 inL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCL The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3- b]pyridin-5-yl)-N--(l-phenylcyclopropyl)benzamide (180 mg, 0.341 mmol, 63 % yield) consistent by LCMS. LC-MS retention time: 1.89 min; m/z (MH+): 529. LC data was recorded on a Shimadzu LC-IOAS liquid chrorαatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetom^'trile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 2: Preparation of 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(l - phenylcyclopropyl)benzamide. Pd(Ph3P)4 (16 mg, 0.014 mmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2j3-b]pyridin-5-yl)-N-(l - phenylcyclopropyl)benzamide (75 mg, 0.14 mmol), trimethylboroxine (40 μL, 0.28 mmol), and Na2CO3 (45 mg, 0.43 mmol) in DMF (1.3 mL) and Water (.13 niL) at room temperature. It was subjected to microwave irradiation: 180 ⁰C for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-methyifuro[2,3-b]pyridm-5-yl)-N- (l-phenylcyclopropyl)benzamide (61 mg, 0.132 mmol, 93 % yield) consistent by LCMS. LC-MS retention time: 1.81 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM, The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 1O mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 3: Preparation of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(l- phenylcyclopropyl)benzamide. AIBN (6.5 mg, 0.040 mmol) was added to a stirring solution of NBS (26 mg, 0.15 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3- b]pyridin-5-yl)-N-(l-ρhenylcyclopropyl)benzamide (61 mg, 0.13 mmol) in CC14 (20 ml). The mixture was heated to 76 ⁰C and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (18.5 mg, 0.158 mmol) and subjected to MW irradiation (150⁰C) for 10 rm^'n. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2x followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product 3-(2-(4-fluoroρhenyl)-3-formylfuro[2,3-b]pyridin- 5-yl)-N-(l-phenylcyclopropyl)benzamide (34 mg, 0.071 mmol, 54 % yield) consistent by LCMS. LC-MS retention time: 1.64 min; m/z (MH+): 477. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4,6x50mm column using a SPD-I OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of the title compound, 2-(4-fluorophenyl)-N~methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)f\ιro[2,3-b]pyridine~3-carboxamide. AIBN (3.6 mg, 0.022 mmol) and NBS (17 mg, 0.095 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-foπnylftιro[2,3-b]pyridin-5-yl)-N-Cl- phenylcyclopropyl)benzaimde (35 mg, 0.073 mmol) in CC14 (10 mL) at 95 ⁰C. It was allowed to stir for 30 min. The reaction was removed from the heat and allowed to stir for 2 min and treated with methanamine (0.184 mL, 0.367 mmol, 2M in THF). The reaction was allowed to stir for 1 hour and concentrated. The residue was diluted with EtOAc and washed with 10% sodium bisulfate, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(3-(l- phenylcyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (4 mg, 7.91 μmol, 11 % yield) consistent by LCMS and NMR. 1 H NMR (500 MHz, DMSOd₆) δ ppm 936 (1 H, s), 8.77 (1 H, d, J-2.14 Hz), 8.54 - 8.62 (1 H, m), 8.41 (1 H, d, J=2.14 Hz), 8.31 (1 H, s), 8.04 - 8.09 (2 H, m), 7.99 (1 H, d), 7.95 (1 H, d, J=7.63 Hz), 7.64 (1 H, t, J=7.63 Hz), 7.43 (2 H, t, J=8.85 Hz), 7.26 - 731 (2 H, m), 7.21 - 7.26 (2 H, m), 7.16 (1 H, t), 2.87 (3 H, d, J=4.88 Hz), 131 (4 H, d, J-7.93 Hz). LC-MS retention time: 1.98 min; m/z (MH+): 506. LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50ram column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H₂CVlO mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C- 18, 4.6 x 150 mm, 3 mm, R₄ = 14.12 min, purity = 95%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, R_t = 14.45 min, purity = 96%.

5-(3-(tert-butyIcarbamoyl)phenyI)-2-(4-fluorophenyl)-N-methylfuro[2,3- b]pyridine-3-carboxamide. Step 1: Preparation of methyl 3-(3-bromo-2-(4- fluorophenyl)furo[2,3-b]ρyridin-5-yl)benzoate. (Diazomethyl)trimethylsilane (467 μL, 0.934 mmol) was added to a stirring solution of 3-(3-bromo-2-(4- fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (350 mg, 0.849 mmol) in MeOH (5.7 niL) and Ether (2.8 mL) at room temperature. It was allowed to stir overnight. The mixture was concentrated and resubjected to the reaction conditions using DCM as the solvent. This was repeated again using THF as the solvent. The reaction was concentrated to give the expected product methyl 3-(3-bromo-2-(4- fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoate (350 mg, 0.821 mmol, 97 % yield) consistent by LCMS. LC-MS retention time: 2.01 min; m/z (MH+): 426, 428. LC data was recorded on a Shimadzu LC-IOAS liquid chromato graph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 niM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 niM ammonium acetate, MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 2: Preparation of methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5- yl)benzoate. 2,4,6-trimethyl-l, 3,5,2 A6-trioxatriborinane (0.236 mL, 1.69 mmol) was added to a stirring solution of methyl 3-(3-bromo-2~(4-fiuorophenyl)furo[2,3- b]pyridin-5~yl)benzoate (360 mg, 0.845 mmol), sodium carbonate (269 mg, 2.53 mmol), Pd(Ph3P)4 (98 mg, 0.084 mmol) in DMF (10 mL) and Water (1.0 mL). It was subjected to MW irradiation (180⁰C) for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO 3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was diluted with MeOH and treated with (Diazomethyl)trimethylsilane (467 μL, 0.934 mmol) to re-esterfy the acid which had formed. It was allowed to stir for 1 hour and then concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 run) to give the expected product methyl 3-(2-(4-fluorophenyl)-3- methylfuro[2,3-b]pyridin-5~yl)benzoate (163 mg, 0.451 mmol, 53 % yield) consistent by LCMS. LC-MS retention time: 1.79 min; m/z (MH+): 362. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograpli equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 mm where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of methyl 3-(2-(4-fiuorophenyl)-3-formylfuro[2_}3-b]pyridin-5- yl)benzoate. AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0,49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5- yl)benzoate (163 mg, 0.451 mmol) in CC14 (40 mL) and was heated to 76 ⁰C. The mixture was allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150⁰C) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2x followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to to give the expected product methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (34 mg, 0.091 mmol, 20 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, DMSO-d₆) 6 ppm 10.31 (1 H, s), 8.79 (1 H, d, J=2.44 Hz), 8.74 (1 H, d, J-2.44 Hz), 8.28 (1 H, s), 8.16 - 8.25 (2 H, m), 8.00 - 8.13 (2 H, m), 7.72 (1 H, t, J=7.78 Hz), 7.49 - 7.57 (2 H₇ m), 3.92 (3 H, s). LC-MS retention time: 1.72 min; m/z (MH+): 376. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 mϊ/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of methyl 3~(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3- b]pyridin-5-yl)benzoate. AIBN (4.6 mg, 0.028 mmol) and NBS (21.6 mg, 0.121 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3- formylfuro[2,3-b]pyridin-5-yl)benzoate (35 mg, 0.093 mmol) in CC14 (5 mL) at 95 ⁰C. It was allowed to stir for 30 min and then allowed to cool and was then treated with methanamine (0.466 mL, 0.932 mmol, 2M in THF) and the reaction was allowed to stir for 10 mm then diluted with MeOH. A ppt formed which was filtered away and the filtrate was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 320 nm) to give to give the expected product methyl 3-(2-(4-fluorophenyl)~3-(methylcarbamoyl)furo[2,3- b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol, 64 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.60 (1 H, d, J=2.14 Hz), 8.44 (1 H, d, J-2.44 Hz), 8.32 (1 H, s), 8.10 (1 H, d, J-7.93 Hz), 7.95 - 8.00 (2 H, m), 7.84 (1 H, d, J=7.63 Hz), 7.59 (1 H₅ 1, J=7.78 Hz), 7.22 - 7.26 (2 H, m), 5.91 (1 H, br. s.), 3.98 (3 H, s), 3.03 (3 H, d, J-4.88 Hz). LC-MS retention time: 1.46 min; m/z (MH+): 405. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile I ^' 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin- 5-yl)benzoic acid. NaOH (0.297 mL, 0.297 mmol, IM aq.) was added to a stirring solution of methyl 3-(2-(4-fϊuorophenyl)-3-(methylcarbamoyl)furo[2,3-b]ρyridin-5- yl)benzoate (24 mg, 0.059 mmol) in MeOH (2 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(2-(4-fluoroρhenyl)-3- (methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (22 mg, 0.056 mmol, 95 % yield) consistent by LCMS. LC-MS retention time: 0.90 min; m/z (MH+): 391. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 6: Preparation of the title compound, 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4- fluorophenyl)-N-memylfuro[2,3-b]pyridine-3-carboxamide. DIEA (31 μL, 0.18 mmol) was added to a stirring solution of 3-(2-(4-fiuorophenyl)-3- (methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (23 mg_> 0.059 mmol), 2- methylpropan-2-amine (20 μL, 0.059 mmol), and HATU (27 mg, 0.071 mmol) in DMF (0.6 mL) at room temperature. It was allowed to stir for 2 hours. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried overNa2SO4, filtered and concentrated to give the expected product 5-(3- (tert-butylcarbamoyl)phenyl)-2-(4-fiuorophenyl)-N~methylfuro[2,3-b]pyridine-3- carboxamide (8 mg, 0.017 mmol, 29 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, DMSO-d₆) δ ppm 8.74 (1 H, d, J=2.14 Hz), 8.55 - 8.61 (1 H, m), 8.39 (1 H, d₅ J=2.44 Hz), 8.16 (1 H, s), 8.07 (2 H, dd, J=8.85, 5.19 Hz), 7.94 (1 H, s), 7.92 (1 H, d, J=7.63 Hz), 7.86 (1 H, d, J-7.93 Hz), 7.59 (1 H, t, J=7.63 Hz), 7.43 (2 H, t, J=8.85 Hz), 2.87 (3 H₉ d, J=4.58 Hz), 1.42 (9 H, s). LC-MS retention time: 1.68 min; m/z (MH+): 446. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H₂OAO mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H₂O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C-18, 4.6 x 150 mm, mm, R_t = 13.66 min, purity = 98%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, R_t = 13.69 min, purity = 98%.

5-(2-chlor o-5-(l -(pyridin-2-yl)cy clopr opylcarb amoyl)p henyl)-2-(4- fIuorophenyI)-N-methylfuro[2,3~b]pyrϊdine-3-carboxamide. Step 1: Preparation of 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid. Cesium carbonate (167 mg, 0.514 mmol) was added to Pd(Ph3P)4 (40 mg, 0.034 mmol), 5- bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (100 mg, 0.342 mmol), 3-borono-4~ chlorobenzoic acid (103 mg, 0.514 mmol) in DMF (3 mL) and Water (0.3 mL) at room temperature. The mixture was degassed 3x:and the reaction was heated to 180 ⁰C in the microwave for 10 min. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was triturated with MeOH to give the expected product 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (59 mg, 0.160 mmol, 47 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 13.22 (1 H, br. s.), 8.36 (1 H, d, J=2.26 Hz), 8.25 (1 H, d, J-2.26 Hz), 8.03 - 8.11 (2 H, m), 7.97 - 8.02 (2 H, m), 7.77 (1 H, d, J=7.78 Hz), 7.55 (1 H, s), 7.41 (2 H, t, J-8.78 Hz). LC-MS retention time: 1.15 min; m/z (MH+): 368. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 2: Preparation of 3-(3-bromo-2-(4-fluorophenyl)fuio[2,3-b]pyridin-5-yl)-4- chlorobenzoic acid. NBS (29.0 mg, 0.163 mmol) was added to a stirring solution of 4-chloro-3-(2-(4-fluorophenyl)furo[23~b]pyridin-5-yl)benzoic acid (50 mg, 0.136 mmol) in THF (4.5 mL) at room temperature. It was allowed to stir for 1 hour. An additional portion of NBS (29 mg, 0.16 mmol) was added it was allowed to stir for 1 hour after which another portion of NBS (29 mg, 0.16 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 10% NaHSO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2₎3-b]pyridin-5-yl)-4~chlorobenzoic acid (57 mg, 0.128 mmol, 94 % yield) consistent by LCMS and NMR. IH NMR (500 MHz, DMSO-d6) δ ppm 8.48 (1 H, d, J=2.14 Hz), 8.19 - 8.24 (2 H, m), 8.17 (1 H, d, J=2.14 Hz), 7.99 - 8.05 (2 H, m), 7.79 (1 H, d, J=8.24 Hz), 7.46 - 7.52 (2 H, m). LC- MS retention time: 1.29 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3- b]pyridin-5-yl)benzoic acid. l,3-bis(diphenylphosphino)propane (28 mg, 0.067 mmol) was added to a stirring solution of palladrum(II) acetate (7.5 mg, 0.034 mmol) and 3-(3~bromo-2-(4-fluorophenyl)furo[2_ϊ3-b]pyridin-5-yl)-4-chlorobenzoic acid (75 mg_f 0.17 mmol) in MeOH (0.6 mL) and DMSO (1.1 mL) at 80 ⁰C in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with ethyl acetate and washed with 1 M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (75 mg, 0.113 mmol, 67 % yield) by LCMS. LC-MS retention time: 2.28 min; m/z (MH+): 427. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C 18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: 5-(2-chloro-5-(l-(pyridin-2-yl)cyclopropylcarbamoyl)ρhenyl)-2-(4- fluorophenyl)-N-methylfuro[2,3-b]pyridiαe-3-carboxamide. DIEA (142 μL, 0.810 mmol) was added to a stirring solution of l-(pyridin-2-yl)cyclopropanamine dihydrochloride (84 mg, 0,405 mmol), 4-chloro-3-(2-(4-fluorophenyl)-3- (methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (115 mg, 0.270 mmol) and HATU (154 mg, 0.405 mmol) in DMF (2.7 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give crude methyl 5-(2-chloro-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)ρhenyl)-2-(4-fluoroρhenyl)furo[2,3-b]pyridine-3~ carboxylate. The crude residue was diluted with MeOH (4 mL) and treated with NaOH (810 μL, 0.810 mmol) in H2O; the reaction was heated to 60⁰C and allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4_f filtered and concentrated to give crude 5-(2-chloro~5-(l-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4- fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid. The crude residue was diluted with DMF (2 mL) and treated with HATU (154 mg, 0.405 mmol), methanamine (675 μL, 1.35 mmol, 2 M in THF) in THF, followed by DIEA (142 μL, 0.810 mmol). The reaction was allowed to stir at room temperature for 1 hour. The mixture was concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 ran) to give the expected product consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 9.40 (1 H, s), 8.52 (1 H, d, J=4,77 Hz), 8.50 (1 H, d, 1=2.01 Hz), 8.44 (1 H, d, J=4.77 Hz), 8.23 (1 H, d, J=2.01 Hz), 8.12 (1 H, d, J=2.01 Hz), 7.97 - 8.09 (3 H, m), 7.78 (1 H, d, J=8.28 Hz), 7.67 (1 H, td, J=7.72, 1.88 Hz), 7.39 - 7.47 (2 H, m), 7.36 (1 H, d, J-8.03 Hz), 7.15 (1 H, dd, J=7.40, 4.89 Hz), 2.83 (3 H, d, J=4.52 Hz), 1.50 - 1.60 (2 H, m), 1.22 - 1.32 (2 H, m). LC-MS retention time: 1.31 min; m/z (MH+): 541. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column:

Phenomenex Gemini Cl C-18, 4.6 x 150 mm, 3 mm, Rt = 9.66 min, purity = 98%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 9.69 min, purity = 98%.

2~(4-fluorophenyl)-N~methyl-5-(2~methyI-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide. Step 1 : Preparation of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4- methylbenzoate. Cs2CO3 (379 mg_? 1.164 mmol) was added to a stirring solution of 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (200 mg, 0.685 mmol), 4-methyl-3- (4,4,5 ,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (269 mg, 1.027 mmol), Pd(Ph3P)4 (158 mg, 0.137 mmol) in 1,4-dioxane (5.7 mL) and Water (1.1 mL). It was heated to 90 ⁰C overnight. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and diluted with MeOH/DCM and treated with TMS-diazomethane (685 μL, 1.369 mmol, 2M in ether). The mixture was allowed to stir for 1 hour. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product methyl 3-(2- (4-fluorophenyl)fUro[2,3-b]pyridin-5-yl)-4-methylbenzoate (250 mg, 0.692 mmol, 100 % yield) by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 8.28 (1 H, d, J=2.26 Hz), 8.16 (1 H, d, J=2.01 Hz), 8.01 - 8.10 (2 H, m), 7.93 (1 H, dd, J=7.91, 1.88 Hz), 7.85 (1 H, d, J=I.76 Hz), 7.49 - 7.57 (2 H, m), 7,36 - 7.44 (2 H, m), 3.86 (3 H, s), 2.34 (3 H, s). LC-MS retention time: 2.55 min; ro/z (MH+): 362. LC data was recorded on a Shimadzu LC- 1 OAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 2: Preparation of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridm~5- yl)-4-methylbenzoate. The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4- fluorophenyl)furo[2,3~b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in DCE (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) the expected product consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δppm 8.41 (1 H, d, J=2.01 Hz)₅ 8.16 - 8.26 (2 H, m), 8.06 (1 H, d, J=2.26 Hz)₁ 7.95 (1 H, dd, J=8.03, 1.76 Hz), 7.87 (1 H, d), 7.45 - 7.57 (3 H, m), 3.86 (3 H, s), 2.34 (3 H, s). LC-MS retention time: 2.85 mm; mix (MH+):440, 442. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0,1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4~ methylbenzoic acid. NaOH (3.3 mL, 3.3 mmol, IM aq) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fiuorophenyl)furo[2,3-b]pyridin-5-yl)-4- methylbenzoate (294 mg, 0.668 mmol) in MeOH (7 mL) and THF (7 mL) at 60 ⁰C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1 M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2~(4-fluorophenyl)furo[2,3- b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol, 97 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 12.90 (1 H, br. s.)_s 8.40 (1 H, d, J=2.26 Hz), 8.18 - 8.25 (2 H₁ m), 8.05 (1 H, d, J=2.26 Hz), 7.92 (1 H, dd, J=7.78, 1.76 Hz), 7.85 (1 H, d, J=I.76 Hz), 7.43 - 7.54 (3 H, m), 2.35 (3 H, s). LC- MS retention time: 2.42 min; m/z (MH+): 426, 428. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4,6x50mm column using a SPD- 1 OAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of 3-(2-(4-fiuorophenyl)-3-(methoxycarbonyl)furo[2,3-b]ρyridm- 5-yl)-4-methylbenzoic acid. l,3-bis(diphenylphosphino)ρroρane (160 mg, 0.387 mmol) was added to a stirring solution of palladium(II) acetate (44 mg, 0.19 mmol) and 3-(3 -bromo-2- (4-fluorophenyϊ)furo [ 2 ,3 -b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol) in MeOH (2.1 mL) and DMSO (4.3 mL) at 80 ⁰C in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO 3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(2-(4-fluorophenyl)-3- (methoxycarbonyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (176 mg, 0.434 mmol, 67 % yield) consistent by LCMS and NMR. 1 H NMR (400 MHz, DMSO-dό) δ ppm 12.95 (1 H, br. s.), 8.42 (1 H, d, J=2.01 Hz), 8.34 (1 H, d, J=2.01 Hz), 8.14 - 8.21 (2 H, m), 7.93 (1 H, dd, J=8.03, 1.76 Hz)₅ 7.84 (1 H₅ d, J-1.76 Hz), 7.45 - 7.53 (3 H, m), 3.89 (3 H₅ s), 2.32 (3 H, s). LC-MS retention time: 2.16 min; ra/z (MH+): 406. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of the titled compound; 2-(4-fluorophenyl)-N-methyl-5-(2- methyl-5-(l-{pyridiri-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3- carboxamide. Hunig's Base (65 μL, 0.37 mmol) was added to a stirring solution of HATU (56 mg, 0.15 mmol), 3~(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2₍3- b]pyridm-5-yl)-4-methylbenzoic acid (50 mg, 0.12 mmol), l-(pyridin-2- yl)cycloρropanamine dihydrochloride (31 mg, 0.15 mmol) in DMF (1.2 mL) at room temperature. It was allowed to stir for 30 min. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, IM NaOH, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give methyl 2-(4-fluorophenyl)- 5-(2-methyl-5-(l-(ρyridm-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3- carboxylate. The crude residue was diluted with MeoH (2 mL) and treated with NaOH (0.617 μL, 0.617 mmol, IM aq). The mixture was allowed to stir at 60⁰C for 1 hour. The mixture was diluted with EtOAc and washed with IM HCl, and sat

NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 2-(4-fluorophenyl)-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid. The residue was diluted with DMF (1.2 ixiL) and treated with HATU (56 mg, 0.15 mmol), methanamine (308 μL, 0.617 mmol, 2M in THF), followed by Himig'sBase (65 μL, 0.37 mmol). The reaction was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm)to give 2-(4- tluorophenyl)-N-methyl-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (19 mg, 0.035 mmol, 29 % yield) consistent by LCMS and NMR. IH NMR (400 MHz₅ DMSO-d6) δ ppm 9.27 (1 H, s), 8.48 - 8.54 (1 H, m), 8.46 (1 H, d, J=4.02 Hz), 8.42 (1 H, d,

J-2.01 Hz), 8.13 (1 H, d, J=2.26 Hz), 8.05 - 8.11 (2 H, m), 7.90 - 7.95 (2 H, m), 7.68 (1 H, td, J=7.78, 1.76 Hz), 7.51 (1 H, d, J-8.78 Hz), 7.41 - 7.47 (2 H, m), 7.36 (1 H, d, J=8.03 Hz), 7.16 (1 H, dd, JK7.O3, 5.27 Hz), 2.85 (3 H, d, J=4.52 Hz), 2.35 (3 H, s), 1.53 - 1.59 (2 H, m), 1.25 - 1.30 (2 H, m). LC-MS retention time: 1.34 min; m/z (MH+): 521. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 mm, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H2O/10 tnM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C-18, 4.6 x 150 mm, 3 mm, Rt = 13.32 min, purity = 97%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 13.90 min, purity = 97%.

2-(4-fluorophenyϊ)-N-methyl-5-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[3,2-b]pyridine-3-carboxamide. Sodium 2'- (dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3~sulfonate (18 mg, 0.034 mmol), PdOAc2 (3.9 mg, 0.017 mmol), Cs2CO3 (168 mg, 0.516 mmol), 4-methyl-3- (4,4,5, 5-tetramethyl-l,3_t2-dioxaborolan-2-yl)benzoic acid (68 mg, 0,26 mmol) was added to a stirring solution of 5-bromo-2-(4-fluoroρhenyl)-N-methylfuro[3,2- b]pyridine~3~carboxamide (60 mg, 0.17 mmol) in DMF (3.1 mL) and Water (310 μL). It was degassed and heated to 60 ⁰C and allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)furo[3,2-b]ρyridin-5-yl)-4-methylbenzoic acid crude. The residue was diluted with DMF (3.1 mL) and treated with HATU (98 mg, 0.26 mmol), l-(pyridin-2-yl)cyclopropanamine dihydrochloride (54 mg, 0.260 mmol), followed by DIEA (150 μL, 0.859 mmol) at room temperature. The reaction was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM NaOH, and sat NaCL The organic phase was dried over Na2SO4, filtered, concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give 2-(4-fluorophenyl)~N-methyl~5-(2-methyl- 5-(l-(pyridm-2-yl)cycloρropylcarbamoyl)phenyl)ftιro[3,2-b]pyridine-3-carboxamide (27 mg, 0.049 mmol, 29 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-dό) δ ppm 9.29 (1 H, s), 8.98 - 9.07 (1 H, m), 8.45 (1 H, d, J-4.02 Hz), 8.25 - 8.34 (3 H, m), 8.10 (1 H, d, J=I.76 Hz), 7.94 (1 H, dd, J=8.03, 1.76 Hz), 7.73 (1 H, d, J=8.53 Hz)₅ 7.67 (1 H, td, J=7.65, 1.76 Hz), 7.50 (1 H, d, J=7.78 Hz), 7.39 - 7.46 (2 H, m), 7.35 (1 H, d, J=8.03 Hz)₅ 7.14 (1 H, dd, J=6.53, 4.77 Hz), 2.91 (3 H, d, J=4.77 Hz), 2.45 (3 H, s), 1.52 - 1.59 (2 H, m), 1.23 - 1.31 (2 H, m). LC-MS retention time: 1.46 min; m/z (MH+): 521. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C-18, 4.6 x 150 mm, 3 mm, Rt = 13.35 min, purity = 98%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 12.68 mill, purity = 98%.

2-(4-fluorophenyI)-N-methyI-5-(3-(l-(pyridin~2- yl)cyclopropylcarbamoyl)phenyl)furo[3,2-b]pyridine-3»carboxamide. Sodium 2'- (dicyclohexylphosphmo)-2,6-dimethoxybiphenyl-3-sulfonate (8.8 mg, 0.017 mmol), PdOAc2 (1.9 mg, 8.6 μmol), Cs2CO3 (84 mg, 0.26 mmol), 3-boronobenzoic acid (21 mg, 0.13 mmol) was added to a stirring solution of 5-bromo-2-(4-fluorophenyl)- N-methylfuro[3,2-b]pyridine-3-carboxamide (30 mg, 0.086 mmol) in DMF (1.6 mL) and Water (160 μL). It was degassed and heated to 60 °C and allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with IM HCl, and sat NaCL The organic phase was dried over Na2SO4, filtered and concentrated to give 3-(2-(4-fluorophenyl)-3~(methylcarbamoyl)furo[3,2-b]pyridin-5-yl)benzoic acid. The residue was diluted with DMF (1.6 mL) and treated with HATU (49 mg, 0.13 mmol), l-(pyridin-2-yl)cyclopropanamine dihydrochloride (27 mg, 0.13 mmol), followed by DΪEA (75 μL, 0.43 mmol) at room temperature. The reaction was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM NaOH, and sat NaCl, The organic phase was dried over Na2SO4_; filtered and concentrated and was purified by preparative reverse phase HPLC on a Cl 8 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(3-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[3,2-b]pvridme-3-carboxamide (12 mg, 0.023 mmol, 27 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 9.44 (1 H, s), 9.09 - 9,18 (1 H, m), 8.73 (1 H, s), 8.46 (1 H, d), 8.39 (1 H, d), 8.27 - 8.35 (3 H, m), 8.19 (1 H, d, J=8.78 Hz), 8.01 (1 H, d), 7.65 - 7.74 (2 H, m), 7.39 - 7.46 (3 H, m), 7.13 - 7.20 (1 H, m), 2.98 (3 H, d, J=4.77 Hz). LC-MS retention time: 1.50 min; m/z (MH+); 507. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x5 Omm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C- 18, 4.6 x 150 mm, 3 mm, Rt = 25.18 min, purity = 99%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 25.85 min, purity = 99%.

2-(4-fluorophenyϊ)-N-methyl-5-(2-methyI-5-(l-(pyridin-2- yl)cyclopropykarbamoyl)phenyl)furo[2,3-c]pyridine-3-carboxamide. Sodium 2^!- (dicyclohexylρhosphmα)-2,6-dimethoxybiphenyl-3-sulfonate (9.8 mg, 0.019 mmol), PdOAc2 (2.2 mg, 9.6 μmol), Cs2CO3 (93 mg, 0.29 mmol), 4-methyl-3-(4,4_>5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (38 mg, 0.14 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2_s3-c]pyridin-5-yl trifluoromethanesulfonate (40 mg, 0.096 mmol) in DMF (1.7 mL) and Water (170 μL). It was degassed and heated to 60 ⁰C and allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)furo[2,3-c]pyridin-5-yl)-4-methylbenzoic acid. The residue was diluted with DMF (1.7 mL) and treated with HATU (55 mg, 0.15 mmol), l-(pyridin-2-yl)cyclopropanamine dihydrochloride (30 mg, 0.15 mmol), followed by DIEA (84 μL, 0.48 mmol) at room temperature. The reaction was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM NaOH, and sat NaCl. The organic phase was dried over Na2SO4, filtered,concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nra) to give 2-(4-fluorophenyl)-N-methyl-5- (2-methyl-5-(l-(pyridm-2-yl)cyclopropylcarbamdyl)phenyl)furo[2,3-c]pyridine-3- carboxamide (5.4 mg, 9.85 μmol, 10% yield)consistent by LCMS and NMR. IH NMR (500 MHz, MeOD) δ ppm 7.68 - 7.73 (1 H, m), 7.10 - 7.18 (1 H, m), 6.75 - 6.82 (2 H₅ m), 6.68 - 6.72 (1 H, m), 6.61 - 6.66 (1 H, m), 6.54 - 6.59 (1 H, m), 6.38 - 6.46 (1 H, m), 6.15 - 6.24 (2 H, m), 6.02 - 6.09 (2 H, m), 5.85 - 5.92 (1 H, m), 1.69 (3 H, s), 1.12 (3 H, s), 0.38 - 0.43 (2 H, m), 0.07 - 0.13 (2 H, m). LC-MS retention time: 0.913 min; m/z (MH+); 521. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% CH3CN/95% H2O/0.1% TFA, Solvent B = 95% CH3CN/5% H2O/0.1% TFA, Start %B = 10, Final %B ~ 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Waters Sunfire C- 18, 4.6 x 150 mm, 3.5 mm, Rt = 5.61 min, purity = 95%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 6.00 min, purity = 96%. Additional HPLC method: Solvent A = 5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B = 95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start %B = 10, Final %B = 100, Gradient time = 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Phenomenex Gemini Cl C-18, 4.6 x 150 mm, 3 mm, Rt = 9.41 min, purity = 97%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt = 9.38 min, purity = 100%.

2-(4-fluorophenyl)-N-methyl-5-(3-(l-(pyridin-2- yl)cyclopropylcarbamoyI)phenyl)furo[2,3-c]pyridine-3-carboxamide. Sodium 2'- (dicyclohexylphosρhino)-2,6-dimethoxybiphenyl-3-sulfonate (9.8 mg, 0.019 mmol), PdOAc2 (2.2 mg, 9.6 μmol), Cs2CO3 (93 mg, 0.29 mmol), 3-boronobenzoic acid (24 mg, 0.14 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-3-

(methylcarbamoyl)furo[2,3-c]pyridin-5-yl trifluoromethanesulfonate (40 mg, 0.096 mmol) in DMF (1.7 mL) and Water (170 μL). It was degassed and heated to 60 ⁰C and allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3- c]pyridin-5-yl)benzoic acid. The residue was diluted with DMF (1.7 mL) and treated with HATU (55 mg, 0.15 mmol), l-(pyridin-2-yl)cycloproρanamine dihydrochloride (24 mg, 0.12 mmol), followed by DIEA (84 μL, 0.48 mmol) at room temperature. The reaction was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM NaOH, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a Cl 8 column using a suitably buffered H2O/Me0H gradient, and concentrated to give 2-(4-fluorophenyl)-N-methyl-5 -(3 -( 1 -(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)furo[2,3-c]pyridine-3-carboxamide (14 mg, 0.028 mmol, 29 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δppm 9.45 (1 H, s), 9.14 (1 H, s), 8.67 (1 H, s), 8.55 - 8.61 (1 H, m), 8.51 (1 H₅ d, J=5.02 Hz), 8.34 (1 H, d, J-7.78 Hz), 8.27 (1 H₅ s), 8.07 (2 H, dd, J=8.78, 5.52 Hz), 7.99 (1 H, d, J=7.78 Hz), 7.80 - 7.91 (1 H, m), 7.64 (1 H, t, J=7.78 Hz)₅ 7.49 (1 H, d, J=8.03 Hz), 7.45 (2 H, t, J=8.91 Hz), 7.25 - 7.34 (1 H, m), 2.89 (3 H₅ d₅ J=4.S2 Hz)₅ 1.58 - 1.69 (2 H, rn), 1.36 - 1.45 (2 H, m). LC-MS retention time: 1.26 min; m/z (MH+): 507. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B₅ a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A = 5% CH3CN/95% H2O/0.1% TFA₅ Solvent B - 95% CH3CN/5% H20/0.1% TFA, Start %B = 10, Final %B = 100, Gradient time - 15 min, Stop time = 18 min, Flow Rate = 1 ml/min. Column: Waters Sunfire C- 18, 4.6 x 150 mm, 3.5 mm, Rt = 13.20 min, purity = 100%; Column: Waters Xbridge Phenyl column 4.6 x 150 mm, 3.5 mm, Rt - 12.12 min, purity = 100%.

2-(4-fluorophenyl)-N-methyl»5-(2-methyl-5-(l-(pyrimidin-2- yl)cyclopropylcarbamoyI)phenyl)furo(2,3-b]pyridine-3-carboxamide. Step 1 : Preparation of 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine. 5-bromo-3- iodopyridin-2-ol (6.7 g, 22 mmol) (Heterocycles. 57, 1, pp 55), l-ethynyl-4- fluorobenzene (4.03 g, 33.5 mmol), copper© iodide (0.255 g, 1.34 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (0.784 g, 1.12 mmol) were combined and evacuated/backfilled with N2 (3x) then diluted with triethylamine (223 mL) and heated to 90 ⁰C for 2 hours. The solvent was evaporated and the residue was dissolved in EtOAc. The organic phase was washed with water (50 niL), brine, dried over Na2SO4, filtered, and concentrated. Trituration with Et2O afforded the expected product 5-bromo-2-(4-fluorophenyl)furo[2,3-b]ρyridine (4.2 g, 14.4 mmol, 64 % yield). IH NMR (400 MHz, DMSOd₆) δ ppm 8.35 - 8.42 (2 H, m), 8.03 (2 H, dd, J=8.78, 5.27 Hz), 7.46 (1 H, s), 7.39 (2 H₅ 1, J=8.91 Hz). LC-MS retention time: 2.36 min; m/z (MH+): 292, 294. LC data was recorded on a Shimadzu LC-IOAS liquid chroraatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 2: Preparation of methyl 3-(2~(4-fluorophenyl)furo[2,3-b]pyridin~5-yl)-4- methylbenzoate. Cesium carbonate (379 mg, 1.164 mmol) was added to a stirring solution of 5-bromo-2-(4-fluoroρhenyl)furo[2,3-b]pyridine (200 mg, 0.685 mmol), 4- methyl-3-(4A5_»5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (269 mg, 1.027 mmol), Pd(Ph3P)4 (158 mg, 0.137 mmol) in 1 ,4-dioxane (5.7 mL) and Water (1.1 mL). It was heated to 90 ⁰C overnight. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and diluted with MeOH/DCM and treated with TMS- diazomethane (685 μL, 1.37 mmol, 2M in ether). The mixture was allowed to stir for 1 hour. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-metliylbenzoate (247 mg, 0.685 mmol, quant) by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 8.28 (1 H, d, J=2.26 Hz), 8.16 (1 H, d, J=2.01 Hz), 8.01 - 8.10 (2 H, m), 7.93 (1 H, dd, J=7.91, 1.88 Hz), 7.85 (1 H₅ d, J=I .76 Hz), 7.49 - 7.57 (2 H_s m), 7.36 - 7.44 (2 H, m), 3.86 (3 H, s), 2.34 (3 H, s). LC-MS retention time: 2.55 min; m/z (MH+): 362. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u CIS 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1 % trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 3: Preparation of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3~b]pyridin-5- yl)-4-metJiylbenzoate, The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0,983 mmol) was added to a stirring solution of methyl 3-(2-(4- fluoiOphenyl)furo[2_f3-b]pyridin-5-yI)-4-methylbenzoate (289 mg_t 0.800 mmol) in dichloroethane (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) the expected product consistent by LCMS and NMR. IH NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1 H, d, J=2.01 Hz), 8.16 - 8.26 (2 H, m), 8.06 (1 H, d, J=2.26 Hz)₉ 7.95 (1 H, dd, J=8.03, 1.76 Hz), 7.87 (1 H₅ d), 7.45 - 7,57 (3 H, m), 3.86 (3 H, s), 2.34 (3 H, s). LC-MS retention time: 2.85 min; m/z (MH+):440, 442. LC data was recorded on a Shimadzu LC-I OAS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifiuoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifiuoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 4: Preparation of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yϊ)-4- methylbenzoic acid. NaOH (3.3 mL, 3.3 mmol, IM aq) was added to a stirring solution of methyl 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4- methylbenzoate (294 mg, 0.668 mmol) in MeOH (7 mL) and THF (7 mL) at 60 ⁰C. It was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(3-bromo-2~(4-fluorophenyl)furo[2,3- b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol, 97 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, DMSOd6) δ ppm 12.90 (1 H, br. s.), 8.40 (1 H₅ d, J=2.2ό Hz), 8.18 - 8.25 (2 H, m), 8.05 (1 H, d, J-2.26 Hz), 7.92 (1 H₃ dd, J=7.78, 1.76 Hz), 7.85 (1 H, d, J=I.76 Hz), 7.43 - 7.54 (3 H, m), 2.35 (3 H, s). LC-MS retention time: 2.42 min; m/z (MH+): 426, 428. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/mm, a gradient of

100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min j a hold time of 1 min_} and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 5: Preparation of tert-butyl 3-(3-bromo-2-(4-fluorophenyi)furo[2,3-b]pyridin-5- yl)-4~methylbenzoate. N,N-Dimethylformamide di-tert-butyl acetal (653 μL, 2.72 mmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3- b]pyridin-5-yl)-4-methylbenzoic acid (290 mg, 0.680 mmol) in toluene (6.8 mL) at 80 ⁰C. The reaction was allowed to stir for 1 hour. The mixture was concentrated to dryness and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ = 254 nm) to give the expected product, tert-butyl 3-(3-bromo-2-(4- fluorophenyl)furo[2,34>3pyridin-5-yl)-4-methylbeπzoate (231 mg, 0.479 mmol, 70 % yield) consistent by LCMS. LC-MS retention time: 2.34 min; m/z (MH+): 482. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 mϊ/mm, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 6: Preparation of methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4- fluorophenyl)furo[2,3-b]pyridine-3-carboxylate. l,3-bis(diphenylphosphino)propane (119 mg, 0.287 mmol) was added to a stirring solution of palladium(IΪ) acetate (32 rag, 0, 144 mmol) and tert-butyl 3-(3-bromo-2-(4-fluorophenyl)furo[2_s3-b]pyridin-5- yl)-4-methylbenzoate (231 mg, 0.479 mmol) in MeOH (1.6 niL) and DMSO (3 mL) at 80 ⁰C in a PARR bomb which was then charged with 300 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with sat. aq. NaHCO3, and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product methyl 5-(5-(tert-butoxycarbonyl)-2-methylρhenyl)-2-(4-fluorophenyl)furo[2_}3- b]pyridine-3-carboxylate (211 mg, 0.457 mmol, 95 % yield) crude by LCMS which was used directly in the next step. LC-MS retention time: 2.32 min; m/z (MH+): 462. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% MeOH / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 7: Preparation of 5-(5-(teτt-butoxycarbonyl)-2-methylphenyl)-2-(4- fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid. NaOH (1.4 mL, 1.37 mmol) was added to a stirring solution of methyl 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2- (4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate (211 mg, 0.457 mmol) in MeOH (2.3 mL) and THF (2.3 mL) at 60 ⁰C. It was allowed to stir for 4 hours. The mixture was diluted with EtOAc and washed with IM HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product5-(5- (tert-butoxycarbonyl)-2-methylphenyl)-2~(4-fluorophenyl)furo[2,3-b]pyridine-3- carboxylic acid (205 mg, 0.457 mmol, quant.) consistent by LCMS crude which was used directly in the next step. LC-MS retention time: 1.88 min; m/z (MH+): 448. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6x5 Omm column using a SPD-IOAV UV- Vis detector at a detector wave length of 22OnM, The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O 7 95% MeOH / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 8: Preparation of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)fυro[2,3- b]pyridin-5-yl)-4-methylbenzoate. HATU (209 mg, 0.550 mmol) was added to a stirring solution of inethanamine (1.2 mL, 2,4 mmol, 2M in THF), DIEA (240 μL, 1.37 mmol) and 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4- fluorophenyl)furo[2,3-b]pyridme-3-carboxylic acid (205 mg, 0.458 mmol) in DMF (4.5 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtO Ac/hexanes gradient, fraction collection at λ = 254 ran) to give the expected product tert-butyl 3-(2-(4- fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (190 mg, 0.413 mmol, 90 % yield) consistent by LCMS and NMR. IH NMR (400 MHz, MeOD) dppm 8.28 (1 H, d, J=2.26 Hz)₅ 8.08 (1 H, d, J=2.01 Hz), 7.99 - 8.06 (2 H, m), 7.92 (1 H, dd, J=8.03, 1.76 Hz), 7.86 (1 H, d, J=1.51 Hz), 7.45 (I H, d_» J=8.03 Hz), 7.30 (2 H, t, J=8.78 Hz), 2.95 (3 H, s), 2.34 (3 H, s), 1.60 (9 H, s). LC-MS retention time: 2.70 min; m/z (MH+): 461. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters SunFire 5u CIS 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% acetonitrile / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

Step 8: Preparation of the titled compound: 2-(4-fluorophenyl)-N-methyl-5-(2- methyl-5-(l-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3~b]pyridine-3- carboxamide, TFA (544 μL, 7.06 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4- methylbenzoate (65 mg, 0.141 mmol) in DCE (1.4 mL) at rt. It was allowed to stir for 2 hours then concentrated. The white solid was taken up in DMF (1.5 mL) and treated with DIEA (123 μL, 0.706 mmol), l-(pyrimidin-2-yl)cyclopropanamine hydrochloride (29.1 mg, 0.169 mmol) followed by HATU (81 mg, 0.212 mmol) at rt. The reaction was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a Cl 8 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(2- methyl-5-(l-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3- carboxamide (45 mg, 0.086 mmol, 61.1 % yield) consistent by LCMS and NMR. IH NMR (300 MHz₉ DMSO-d6) d ppm 9.19 (1 H, s), 8.66 (2 H, d, J=4.76 Hz), 8.45 - 8.57 (1 H, m), 8.40 (1 H, d, J=I .83 Hz), 8.10 (1 H, d, J=1.83 Hz), 8.00 - 8.08 (2 H, m), 7.85 - 7.94 (2 H, m), 7.35 - 7.50 (3 H, m), 7.26 (1 H, t, J-4.76 Hz), 2.83 (3 H, d, J=4.39 Hz), 2.31 (3 H, s), 1.55 - 1.67 (2 H_} m), 1.27 - 1.39 (2 H, m). LC-MS retention time: 1.75 min; m/z (MH+): 522. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters XBridge 5u Cl 8 4.6x50mm column using a SPD-10AV UV- Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/mm, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% MeOH / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

6-(N-ethyImethylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(l- (pyridin-2-yl) cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3- carboxamide. 6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3- (methylcarbamoyl)pyrazolo[l,5-a]pyridin-5-yl trifluoromethanesulfonate (0.07 g, 0.13 mmol, 1 eq), 4-methyl-N-(l-(pyridin-2-yl)cyclopropyl)-3-(4,4_J5,5-tetrametliyl- l,3,2-dioxaborolan-2-yl)benzamide (0.054 g, 0.14 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0045 g, 0.0039 mmol, 0,03 eq) and cesium carbonate (0.12 g, 0.39 mmol, 3 eq) were dissolved in 1 ,4-dioxane (10 ml) and water (2 ml). Nitrogen gas was passed through the solution and the reaction was heated at 90 ⁰C for 14 h. The solution was filtered through celite. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield : 22 mg (26 %). ¹HNMR (400MHz, CD₃OD): δ 1.12 (broad s, 3H), 1.35 (s, 2H), 1.66 (s, 2H), 2.34 (s, 3H), 2.85 (s, 3H)_} 3.00-332 (br, 3H), 3.51 (br, 2H), 7.13 (m, IH), 7.24 (m, 2H), 7.46 (m, 2H), 7.68 (m, IH)₅ 7.97 (m, 4H), 8.0 (s, IH), 8.41- 8.42 (d, J= 4 Hz, IH), 8.92 (s, IH). LCMS : (ES+) m/z = 641.2 (M+H) Method: Column-Ascentis Express C18 (5X2.1mm~2.7μm); Mphase A : 2% MeCN -98% H₂O-IOmM NH₄COOH; Mphase B : 98% MeCN - 2% H₂O-IOmM NH₄COOH Flow: lmL/Min; RT min : 1.796; Wavelength : 220 nm. HPLC Method : SUNFIRE CIS (4.6X150)mm, 3.5 micron; Buffer : 0.05% TFA in water pH 2.5; Mobile Phase A : Buffer : MeCN (95:5); Mobile Phase B : MeCN :Buffer (95:5); FLOW : lml/min; Wavelength : 254 nm, RT min :8.675; Purity: 96.6 %.

6-(N-ethylmethylsulfonainido)-2-(4-fluorophenyi)-N-methyl-5-(3-(l~(pyrϊdin-2- yl)cyclopropykarbamoyI)phenyI)pyrazoIoIl,5-a]pyridine-3-carboxamide. 6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[l,5- a]pyridin-5-yl trifluoromethanesulfonate (0.1 g, 0.17 mmol, leq), N-(l-(pyridin-2- yl)cyclopropyl)-3-(4_}4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.0.65 g, 0.18 mmol, l.leq), tetrakistriphenylphosphine palladium (0.0058 g, 0.0051 mmol, 0.03 eq) and cesium carbonate (0.165 g, 0.51 mmol, 3eq) were dissolved in 1,4- dioxane (10 ml) and water (2 ml) and the reaction was heated at 90 °C for 14 hours. The solution was filtered through celiete. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26 %) ¹HNMR (400MHz, CD₃OD): δ. 1.05 (t, J= 8 Hz, 3H), 1.65-1.66 (m, 2H), 1.78-1.82 (m, 2H), 2.89 (s, 3H), 3.20 (s, 3H), 3.62 (br s, 2H), 7.28-7.30 (t, J = 7.76 Hz, 2H), 7.57 (br s, IH), 7.67 (t, J= 7.72 Hz, IH), 7.75 (d, J= 8.20 Hz, IH), 7.86-7.88 (m, 3H), 7.96 (s, IH)₅ 8.02 (d, J= 2.09 Hz, IH), 8.18 (br, IH), 8.23 (s, IH), 8.55 (d, J= 5.32 Hz, IH), 8.98 (s, IH). LCMS : (ES+) m/z = 627.2 (M+H); Method: Column-Ascentis Express Cl 8 (5X2. lmm-2.7μm); Mphase A : 2% MeCN -98% H₂O-IOmM NH₄COOH; Mphase B : 98% MeCN ~ 2% H₂O-IOmM NH₄COOH; Flow: lmL/Min; RT min : 1.768; 3-iodo-4-methylbenzoic acid. Methyl-3-Iodo-4-methylbenzoate (3 g, 109 mmol, 1 eq) dissolved in MeOH (30 ml) was added sodium hydroxide (1.3 g, 327 mmol, 3 eq) followed by the addition of water (15 ml). The above solution was stirred at room temperature for 14 h. The solution was concentrated under vacuum, and then added water. The pH of the reaction was bought to 3 using Cone. HCl. The solid obtained was filtered and dried under vacuum, Yield: 2.7 g (96 %). ¹HNMR (400MHz, DMSO-d6): δ 2.44 (s, 3H), 7.45 (d, 7- 8.00 Hz ,1H), 7.85 (d, J= 3.18 Hz, IH), 8.31 (s, IH).

3-iodo-4-raethyl-N-(l-(pyrϊdin-2-yl)cyclopropyl)ben2;amide. 3-Iodo-4- methylbenzoic acid (2.5 g, 9.5 mmol, 1 eq), l-(ρyridin-2-yl)cycloproρanamine (1.41 g, 10.4 mmol, 1.1 eq), EDCLHCl (2.1 g, 11.4 mmol, 1.2 eq), HOBT (1.5 g, 11.4 mmol, 1.2 eq) and DIPEA (4.9 ml, 28.62 mmol, 3 eq) were dissolved in DCM and the above solution was stirred at room temperature for 18 h. Water was added and product was extracted with DCM. The organic layer was concentrated and the crude product crystallized using dichloromethane and hexane. Yeild: 2.3 g (55 %). ¹HNMR (400MHz, DMSO-d₆); δ 1.26 (m, 2H), 1.53 (m, 2H), 2.43 (s, 3H), 7.13 (m, IH), 7.29 (d, J= 8.00 Hz , IH), 7.44 (d, IH), 7.67 (t, J= 3.46 Hz, IH), 7.87 (d, J- 3.24 Hz, IH), 8.38 (s, IH), 8.44 (d, J= 1.10 Hz, IH), 9.29 (s, IH).

4-methyl-N-(l-(pyridm-2-yI)cyclopropyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamide. 3-Iodo-4-methyl-N-(l-(pyridin-2- yl)cycloproρyl)benzamide (2.2 g, 5.8 mmol, 1 eq), Bispinnacolatodiboron (2.21 g, 8.7 mmol, 1.5 eq), Pd(dppf)Cl₂ (0.18 g, 0.23 mmol, 0.04 eq) and Potassium acetate (1.7 g, 17.4 mmol, 3 eq) were dissolved in DMF and nitrogen was purged for 15 minutes. The above solution was stirred at 90 ⁰C for 15 h. The solution was filtered through celiete, and water was added to the filtrate which was extracted with ethylacetate. The crude product was purified by combifiash chromatography to obtain an off white solid. Yield: 1.5 g (68 %). ¹HNMR (400MHz, DMSO-d₆): δ 1.25 (s, 2H), 1.32 (s, 12H), 1.54 (s, 2H), 2.53 (s, 3H), 7.13 (m, IH), 7.29 (m, 2H), 7.69 (t, J= 7.48 Hz, IH), 7.92 (m, IH), 8.18 (s, IH), 8.45 (d, IH), 9.29 (s, IH). LCMS : (ES+) m/z = 379 (M+H). Method: Column-Chromolith SpeedROD Cl 8 (4.6X30); Mphase A : 10%MeOH-90%H₂O-0.1%TFA; Mphase B : 90% MeOH-10%H₂O- 0.1%TFA; Flow : 5mL/Min; RT min : 1.658; Wavelength : 220 nm.

3-iodo-N-(l~(pyridin-2-yl)cyclopropyl)benzamide. 3-Iodobenzoic acid (2.7 g, 11.1 mmol, 1 eq), l-(pyridin-2-yl)cyclopropanamine (1.5 g, 11.1 mmol, 1 eq), EDCLHCl (3.2 g, 16.7 mmol, 1.5 eq}, HOBT (2.2 g, 16.7 mmol, 1.5 eq) and DIPEA (6 ml, 33.5 mmol, 3 eq} were dissolved in DCM and the resulting mixture was stirred at room temperature for 18 hours. Water was added to the mixture and the product was extracted with DCM. The organic layer was concentrated and the product crystallized using dichloromethane and hexane. Yield : 2.3 g (57 %). ¹HNMR

(400MHz, DMSO-de}: δ 1.26 (m, 2H), 1.54 (m, 2H), 7.13 (t, J- 4.04 Hz₉ IH), 7.29 (m, 2H), 7.69 (t, J= 8.06 Hz, IH), 7.92 (d, J= 3.05 Hz, 2H), 8.29 (s, IH), 8.45 (d, / = 4.56 Hz, IH), 9.33 (s, IH).

N-(l-(pyrid in-2-yl) cy clopr opyl)-3-(4 ,4,5,5-tetr amethyl-l ,3,2-diox ab orolan-2- yl)benzamide. 3-Iodo-N-(l-(ρyridin-2-yl)cycloρropyl)benzamide (1 g, 2.7 mmol, 1 eq), Bispinnacolatodiboron (1.04 g, 4.1 mmol, 1.5 eq), Pd(dppi)Cl₂ (0.044 g, 0.054 mmol, 0.02 eq) and Potassium acetate (1.04 g, 13.5 mmol, 3 eq) were dissolved in DMF and nitrogen was purged for 15 minutes, and the above mixtuire was stirred at 90 ⁰C for 15 h. The solution was filtered through celiete, and water was added to the filtrate which was then extracted with ethylacetate. The crude product was purified by combiflash chromatography to get of off white solid. Yield : 0.7 g (70 %). 1HNMR (400MHz, DMSO-d₆): δ 1.27 (m, 2H), 1.32 (s, 12H), 1.54 (m, 2H), 7.12 (s, IH), 7.30 (d, J- 8.00 Hz, IH), 7.49 (X, J= 7.56 Hz, IH), 7.65 (t, J= 3.44 Hz, IH), 7.80 (d, J= 7.32 Hz, IH), 8.03 (m, IH), 8.24 (s, IH), 8.44 (m, IH), 9.35 (s, IH).

4-(benzyloxy) pyridine-3-amine. 4-(benzyloxy)-3-nitropyridine (15 g, 65 rnmol, 1 eq) was dissolved in THF, then Raney Nickel (2.25 g, 10 % w/w) (washed with THF) was added under nitrogen atmosphere and the reaction was stirred at room temperature with 2 kg hydrogen pressure for 6 h. The reaction solution was filtered through celite and the filtrate was concentrated under vacuum to get brown oil. The product was taken to the next step without purification. Yield : 12.3 g (94 %). 1HNMR (400MHz, DMSO-d₆): δ 4.86 (s, 2H), 5.18 (s, 2H), 6.88 (d, IH₅ J= 5.32 Hz), 7.31 (t, IH, J- 3,90 Hz), 7.4 (t, 2H, J- 5.08 Hz)₅ 7.5 (t, 2H, J- 8.08 Hz), 7.71 (d, J= 2.05 Hz, IH), 7.89 (s, IH).

N-(4-(benzyloxy)pyridin-3-yl)-N-(methylsulfonyl)methane sulfonamide. 4- (Benzyloxy)-3-nitropyridine (14 g, 69.8mmol, 1 eq) was dissolved in dichloromethane and cooled to 0 ⁰C. Then added TEA (29.2 ml, 209.6mmol, 3 eq), followed by the addition of potassium carbonate (9.96g, 69.8mnaol, leq) at 0 ⁰C and stirred for 15 minutes. Methane sulfonyl chloride (2Og, 174mmol, 2.5eq) was added slowly at 0 ⁰C to the above mixture and stirred for 14 h. After the completion of reaction, monitored by TLC, the reaction mixture was diluted with water and organic layer was separated. Water layer was extracted twice with 200 ml of dichloromethane, and the combined dichloromethane mixture was washed with water (500 ml) and brine (500 ml). The organic solution was concentrated under vacuum to yield the pure product. Yield: 19.5 g (78 %). ¹HNMR (400MHz, DMSO-d₆): δ 3.47 (S₅ 6H)_S 5.35 (s, 2H), 7.32 (d, J= 5.76 Hz₅ IH), 7.40-7.49 (m, 3H), 7.51 (t, J= 4.12 Hz, 2H)₅ 8.52. (d, J= 5.68 Hz, IH), 8.57 (s, IH).

N-(4-(benzyloxy) pyridin-3-yl) methane sulfonamide. Tetrabutylammonium fluoride 1 M in THF (12.2 ml, 42 mmol, 2.5 eq) was added to a solution of N-(4- (benzyloxy) pyridin-3-yl)-N-(methylsulfonyl) methane sulfonamide (6 g, 16.8 mmol, 1 eq) in THF at room temperature. The reaction mixture was refluxed at 60 ⁰C for 10 h. The solution was concentrated completely and diluted with water (5 mL) and was allowed to stir for 15 minutes. The solid precipitated was filtered, washed with water and dried under vacuum yielding the expected product as a pale brown solid. ¹HNMR (400MHz, DMSOd₆): δ 3.35 (s, 3H), 5.27 (s, 2H), 7.21 (d, J= 5.64 Hz,,lH), 7.36- 7.54 (m, 3H), 7.54 d, J= 7.28 Hz, 2H), 8.30 (s, IH), 8.33 (d, J - 5.64 Hz, IH), 9.34 (s, IH).

tert-butyl 4-(benzyloxy) pyridin-3-yl (methylsulfonyl) carbamate. N-(4- (benzyloxy) pyridin-3-yl) methane sulfonamide (3 g, 10 mmol, 1 eq) was dissolved in THF and cooled to 0 ⁰C. Then TEA (4.4 ml, 32.1 mmol, 3 eq) and DMAP (0.13 g, 1.07 mmol, 0.1 eq) were added and stirred for 15 minutes. Boc-anhydride (2.3 g, 10 mmol, 1 eq) was added slowly at 0 ⁰C and the mixture was stirred at room temperature for 14 h. The solution was concentrated and diluted with water and the product was extracted twice with dichloromethane (125 ml) and purified by combiflash chromatography using 12g column and 50 % ethyl acetate/hexane as the eluent. Yield : 3.1 g (77 %). ¹HNMR (400MHz, DMSOd₆): δ 1.33 (s, 9H), 3.41 (s, 3 H), 5.32 (d, J= 10.4 Hz, 2H), 7.28 (d, J= 5.76 Hz, IH), 7.30-7.46 (m, 5H), 8.47 (s, IH), 8.47 (d, J= 5.68 Hz, IH).

N- Amino tert-butyl 4-(ben2yloxy)pyridin-3-yI(niethyIsulfonyl) carbamate. To a cooled solution of tert-butyl 4-(benzyloxy) pyridin-3-yl (methylsulfonyl) carbamate (1 g, 1 eq) in dichloromethane was added O-(mesitylsulfonylhydroxylamine) (0.85 g, 1.5 eq) in dichloromethane, the solution was stirred at 0 ⁰C for 20 minutes. The ice bath was removed and was stirred at room temperature for 7 h. The reaction mixture was concentrated at room temperature and re-dissolved in a mixture of dichloromethane and methanol (10/1), and then re-concentrated. The solid was placed under high vacuum yielding white foam which was taken to the next step without purification. Yield: 1.3 g. LCMS : (ES+) m/z observed 394.0.

Ethyl 5-(benzyloxy)-6-(N~(tert-butoxycarbonyl) methylsulfonamido)-2-(4- fluorophenyl)pyrazolo[ϊ,5-a] pyridine-3-carboxylate, Ethyϊ-3(4- fluorophenylpropiolate) (0.87 g, 2.8 mmol, 1 ,3 eq) was dissolved in DMF and cooled to 0 °C. To the above solution Potassium carbonate (1.68 g, 8.8 mmol, 4 eq) was added, and the reaction mixture stirred for 15 minutes. Subsequently, N-amino tert- butyl 4-(benzyloxy)pyridin-3-yl(methylsulfonyl)carbamate (1.2 g, 2.2 mmol 1 eq) dissolved in DMF, was added to the above mixture, which was then stirred at room temperature for 24 h. The solution was filtered through celite and purified by combiflash chromatography using 35 % ethyl acetate/hexane as eluent. Yield : 0.37 g (22 %). ¹HNMR (400MHz, DMSOd₆): δ 1.21-1.25 (t, J= 7.08 Hz, 3H), 1 ,33 (s, 9H), 3.49 (s, 3H), 4.20-4.25 (m, 2H), 5.37-5.45 (m, 2H), 7.33 (t, J= 8.9 Hz, 2H), 7.42 (m, 3H), 7.50 (d, J- 6.8 Hz₅ 2H), 7.57 (s, IH), 7.78 (m, 2H), 9.28 (s, IH). LCMS : (ES+) m/z = 584.0 (M+H).

Ethyl 5-(benzyloxy)-2-(4-fluorophenyl)-6-(methylsulfonamido)pyrazolo[l,5- a] pyridine-3-carboxylate. Ethyl 5-(benzyloxy)-6-(N-(tert~ butoxycarbonyl)methylsul fonamido)-2-(4-fluorophenyl)pyrazolo [ 1 ,5 -a]pyridine- 3 - carboxylate (0.32 g, 0.54 mrnol, 1 eq) was dissolved in dichloromethane and cooled to 0 ⁰C. Then added trifluoroacetic acid (3.2 ml). The above mixture was stirred at room temperature for 12 h. The solution was concentrated and the pH was brought to 8 and extracted with dichloromethane. The organic layer was concentrated yielding the desired product and was taken to the next step without further purification. Yield : 0.23 g (88 %). ¹HNMR (400MHz, DMSO-d₆): δ 1.21-1.24 (t, 3H), 3.33 (s, 3H), 4.1- 4.23 (q, 2H), 5.39 (s, 2H), 7.27 (t, J= 5 Hz, 2H), 7.38 (d, J= 2 Hz, IH), 7.43 (m, 2H), 7.53 (s, IH), 7.61 (d, J= 2 Hz, 2H), 7.78 (t, J= 6 Hz, 2H), 8.73 (s, IH)₉ 9.58 (s, IH). LCMS : (ES+) m/z = 484.0 (M+H).

Ethyl 5-(benzyioxy)-6-(N-ethylmethylsulfonamido)-2-(4- fluorophenyl)pyrazo-θ[l,5-a]pyridine-3-carboxylate. Ethyl 5-(benzyloxy)-2-(4- fluorophenyl)-6-(methylsulfonamido)pyrazolo [ 1,5 -a] pyridine-3 -carboxylate (0.2 g, 0.41 mmol, 1 eq) was dissolved in DMF and cooled to 0 ⁰C. Potassium carbonate (0.171 g, 1.6 mmol, 3 eq) was then added and the reaction mixture stirred for 15 minutes. Ethyl iodide (0.037 ml, 0.45 mmol, 1.1 eq) was added slowly dropwise and the resulting mixture was stirred at room temperature for 4 h. The solution was concentrated completely and diluted with water and the product was extracted with dichloromethane twice, The combined organic extracts were washed with water and concentrated yielding the desired product. Yield : 0.16 g (76 %). ¹HNMR (400MHz, DMSOd₆): δ 1.074.10 (t, J= 7.16 Hz, 3H), 1.21-1.24 (t, 3H), 3.04 (s, 3H), 3.64 (m, 2H), 4.19-4.24 (q, J= 7.04 Hz, 2H), 5.38 (s, 2H)₁ 7.28 (t, J= 8.8 Hz, 2H), 7.42-7.54 (m, 3H), 7.57-7.65 (m, 3H), 7.77-7.95 (m, 2H), 9.02 (s, IH). LCMS : (ES+) m/z = 512.0 (M+H).

5-(benzyloxy)~6-(N~ethylmethylsuIfonamido)-2-(4~fluorophenyl)pyrazoIo[l,5- a]pyridine-3-carboxylic acid. Ethyl 5-(benzyloxy)-6-(N-ethylmethyisulfonamido)- 2-(4-fluorophenyl)pyrazolo[l,5-a]pyridine-3 -carboxylate (0.15 g, 0.29 mmol, 1 eq) was dissolved in ethanol. Then sodium hydroxide (0.035 g, 1.17 mmol, 3 eq) was added, followed by the addition of water (1 ml). The reaction was warmed to 45 ⁰C for 14 h. The solution was concentrated and diluted with water and the pH of the reaction was brought to 3 using Cone. HCL The solid precipitated was filtered and dried under vacuum. Yield : 0.12 g (86 %). ¹HNMR (400MHz, DMSOd₆): δ 1.06- 1.10 (t, J = 7.14 Hz₅ 3H)₅ 3.01 (s, 3H), 3.62 (m, 2H), 5.34 (s, 2H)₅ 7.27 (t, J = 8.9 Hz₅ 2H), 7.32-7.46 (m, 4H), 7.56 (d, J- 7.0 Hz, 2H), 7.63 (s, IH), 7.80 (t, J= 4.77 Hz, 2H), 8.98 (s, IH). LCMS : (ES+) m/z = 484.0 (M+H).

5-(benzyloxy)-6-(N-ethylmethyIsulfonamido)-2-(4-fluorophenyl)-N- methyIpyrazolo[l,5-a]pyridine-3-carboxamide. 5-(Benzyloxy)-6-(N- ethylmethylsulfonamido)~2-(4-fluorophenyl)pyrazolo [ 1 ,5-a]pyridme-3-carboxylic acid (0.11 g,0.22mmol, 1 eq), EDCLHCl (0.048 g, 0.25mmol, 1.1 eq), HOBT (0.036 g_}0.27mmol, 1.2 eq), DIPEA (0.12 ml, 0.68mmol, 3 eq) were dissolved in dichloromethane and the reaction was stirred at room temperature for 10 minutes. Then Methylamine (1 M in THF, 0.6 ml, 5 eq) was added to the above solution and the reaction was stirred at room temperature for 14 h. Finally, the mixture was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with water, dried and concentrated. Yield : 0.1 g (90 %). ¹HNMR (40OMHz₅ DMSOd₆): δ 1.06 (t, J= 7.12 Hz, 3H), 2.77 (s, 3H), 3.00 (s, 3H), 3.62 (br m, 2H), 5.30 (s, 2H), 7.307.32 (m, 3H), 7.33 (d, J= 5.8 Hz , IH), 7.40-7.43 (m, 2H), 7.53-7.55 (m, 2H), 7.81 (t, J- 3.52 Hz, IH), 7.95 (s, 2H), 8.88 (s, IH). LCMS : (ES+) m/z = 497.0 (M+H).

6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyI)-5-hydroxy-N- methylpy razolo [ 1,5-a] py ridine-3-carboxamide. 5 -(B enzyloxy)- 6-(N- ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[l,5-a]ρyridine-3- carboxamide (2.5 g, 5 mmol, 1 eq) was dissolved in dichloromethane and cooled to - 78 ⁰C. Tetrabutylammonium iodide (0.19 g, 0.5 mmol, 0.1 eq) was added to the above mixture followed by slow dropwise addition OfBCl₃ (25 ml) at -78 ⁰C. The above solution was stirred at room temperature for 14 h. The solution was quenched with 10% sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane solution was evaporated to get off- brown solid. Yield : 1.6 g (79 %). ¹HNMR (400MHz, DMSOd₆): δ 1.08 (t, J= 7.14 Hz₅ 3H)_S 2.71 (d, J- 4.52 Hz, 3H), 3.11 (s, 3H), 3.62 (q, J= 6.92 Hz, 2H), 7.14 (s, IH), 7.30 (t, J= 8.86 Hz , 2H), 7.57 (d, J= 4.56 Hz, IH), 7.81-7.82 (m, 2H), 8.72 (s, IH), 11.32 (br s, IH). LCMS : (ES+) m/z = 407.0 (M+H). 6-(N-ethyImethylsulfonamido)-2-(4-fluorophenyI)-3~

(methykarbamoyl)pyrazolo[l,5-a]pyridin-S-yl trifluoromethanesulfonate. 6-(N- ethylniethylsulfonamido)-2-(4-fluorophenyl)-5-hydroxy-N-methylpyrazolo[l,5- a]pyridine-3-carboxamide (0.2 g, 0.49 mmol, 1 eq) was dissolved in dichloromethane and cooled to 0 ⁰C. Then triethylamine (0.2 ml, 1.47 mmol, 3 eq) was added, followed by the portion- wise addition of N-

Phenylbis(Trifluoromethanesulphonamide) (0.21 g, 0.58 mmol, 1.2 eq). Then the reaction was stirred at room temperature for 2 h. Water was added to the above mixture which was then extracted with dichloromethane. The crude product was purified by combifiash chromatography using 20 % ethyl acetate/hexane as the eluent. Yield : 0.07 g (70 %). LCMS : (ES+) m/z = 539.0 (M+H).

0-(mesityIsulfonyl)hydroxyIamϊne. Ethyl N-hydroxyacetimidate (10.3 g, 47 mmol, 1.1 eq) and triethylamine (25.5 ml, 94 mmol, 2 eq) were dissolved in DMF (40 ml, 2 vol) and the mixture cooled to 0 ⁰C. O-mesitylene chloride (20 g, 47 mmol, 1 eq) was then added portionwise and the mixture stirred at 0 ⁰C for 45 minutes. The above solution was poured into ice water, and solid obtained was filtered and washed with water. Yield : 23 g (92 %). ¹HNMR (400MHz₅ DMSO-d6): δ 1.16 (t, 3H), 2.03 (s, 3H), 2.31 (s, 3H), 2.64 (s, 6H), 3.89 (q, 2H), 6.96 (s, 2H).

Ethyl N-mesitylsulfonyloxyacetimidate (20 g, 65.7 mmol, 1 eq) was dissolved in 1,4- dioxane (6 ml) and the solution was cooled to 0 °C, To the mixture was added dropwise Perchloric acid (10 m), and the reaction mixture was then stirred at 0 ⁰C for 45 minutes. The solution was poured into ice water, and the solid precipitated was filtered and washed with water and dried for 15 minutes in vacuum. The sample was stored in plastic container at -20 ⁰C. ¹HNMR (400MHz, DMSOd6): δ 2.32 (s, 3H), 2.64 (s_f 6H), 4.98 (br peak, 2H), 6.99 (s, 2H).

Ethyl 3-(4-fluorophenyl)propioIate. 4-Fluorophenylacetylene (1 g, 8.3 mmol, 1 eq) was dissolved in diethylether and cooled to -78 ⁰C. The mixture was added n-butyl lithium (6.9 ml, 2 eq) dropwise slowly at -78 ⁰C and allowed to stirr at -78 ⁰C for 2 hours. Later Ethyl chloroformate (3.06 ml, 33.3 mmol, 4 eq) cooled to -78 ⁰C was added to the above solution as fast as possibly, and the mixture was allowed to stir for 1 h at -78 ⁰C. The solution was quenched with saturated ammonium chloride solution, and the product was extracted with ethylacetate and purified by silica column (60-120) using 5% ethylacetate/hexane as eluent to obtain an off pale brown solid. Yield: 1.3 g (81 %). ¹HNMR (400MHz₅ DMSOdβ): δ 1.35 (t, J= 7.14 Hz, 3H)_} 4.30 (q, J- 7.14 Hz, 2H), 7.07 (t, J- 4.33 Hz, 2H)₅ 7.59 (m, 2H).

All the Prep HPLC purifications were run at following conditions until noted otherwise except for the other conditions that are mentioned in individual procedures. Solvent A: 10% MeOH-90% H₂O-0.1% TFA; Solvent B: 90% MeOH- 10% H₂O- 0.1% TFA; Column: Phenomenex-LUNA AXIA 5 u 21x100 mm S5. LCMS methods: All LCMS analysis conditions used method 1 except mentioned in individual procedure. Method 1: Start % B: 0; Final % B: 100; Gradient time: 4 min; Stop time: 5 min; Flow rate: 5 ml/min; Wavelength: 220; Solvent A: 10% MeOH / 90% H₂O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H₂O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: Phenomenex-hma 3.0 x 50 mm SlO.

2~(4-fluorophenyl)-6-(2-methoxy-5-(2-phenyϊpropan-2'-ylcarbamoyl)phenyl)-N- methylimid azo [ 1 ,2-a] py ridine-3-carboxamide.

Step 1: Preparation of compound 1. To a solution of ethyl 3-(4-fiuorophenyl)-3- oxopropanoate (0.42 g, 2.01 mmol) in DCM (8.0 mL) cooled at 0 ⁰C was added tetra- n-butylammonium tribromide (0.97 g, 2.01 mmol). The reaction mixture was stirred at 0 ⁰C for 2 hrs and then at rt for 16 hrs. The reaction mixture was charged to a 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-80 % EtOAc in hexane, The fractions containing the desired product were concentrated to yield compound 1 (0.50 g, 1.73 mmol, 86 % yield) as a clear oil. LC/MS m/z 288 (M+H)⁺ 289.04, RT = 2.44 min; IH NMR (400 MHz, CHLOROFORM-tf) ppra 7.94 - 8.00 (2 H, m), 7.06 - 7.13 (2 H, m), 5.61 (1 H, s), 4.20 (2 H, q, J-7.30 Hz), 1.10 - 1.21 (3 H, m).

Step 2: Preparation of compound 2. To a solution of compound 1 (1.5 g, 5,2 mmol) in Ethanol (30 mL) was added 5-bromopyridin-2-amine (3.1 g, 18,0 mmol). The reaction was stirred at 70 ⁰C under nitrogen for 16 hrs. The solvent was removed through vacuum. The reaction residue was dissolved in EtOAc, washed with sat NaHCθ₃ and water, dried over anhydrous Na₂SO,*, filtered and concentrated to yield a yellow solid. The solid was dissolved with DCM and charged to a 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-60 % EtOAc in hexane. The fractions containing the desired product were concentrated to yield compound 2 (0.7 g, 1.9 mmol, 36 % yield) as a pale yellow solid. LC/MS m/z 363 (M+H)⁺ 363.2, RT = 2.90 min [Phenomenex Luna C18 4.6 x 50 mm-4 min gradient from 0-100% (A: 95/5/10mm H₂O/ACN/10mM ammonium acetate; B: 95/5/10mm ACN/H₂O/10mM ammonium acetate)]; IH NMR (500 MHz, DMSO-D6) ppm 9.45 (1 H, d, J-1.83 Hz), 7.81 - 7.85 (2 H, m), 7.80 (1 H, s), 7.74 - 7.77 (1 H, m), 7.28 - 7.33 (2 H, m), 4.29 (2 H, q, J=7.22 Hz), 1,20 (3 H, t, J=7.17 Hz).

Step 3: Preparation of compound 3. To a solution of compound 2 (0.42 g, 1.16 mmol) in THF (5 mL) and MeOH (1 mL) was added 1.0 N NaOH (2.3 mL, 2.3 mmol). The reaction mixture was stirred at rt for 16 hrs. The solvent was removed through vacuum. The residue was diluted with EtOAc, washed with 1 N HCl, sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield compound 3 (0.39 g, 1.16 mmol, 100 % yield) as a white solid. LC/MS m/z 334 (M+H)⁺ 335.15, RT = 1.48 min [Phenomenex Luna Cl 8 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)].

Step 4: Preparation of compound 4. To a solution of compound 3 (0.39 g, 1.16 mmol) in DMF (5 mL) was added EDC (0.34 g, 1.75 mmol), HOBT (0.27 g, 1.75 mmol), methylamine hydrochloride (0.16 g, 2.33 mmol) and DIEA (0.61 mL, 3.49 mmol). The reaction mixture was stirred at 50 ⁰C for 2 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO₃, sat. NaCl. The white solid was filtered and washed with EtOAc, then dried to yield compound 4 (0.20 g, 0.57 mmol, 49 % yield) as a yellow solid. LC/MS m/z 347 (M+H)⁺ 348, RT = 1.24 min [Phenomenex Luna Cl 8 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOHZH₂CVTFA)].

Step 5: Preparation of compound 5, To a solution of compound 4 (0.058 g, 0.17 mmol) in dioxane (1 mL) and Water (0.2 mL) was added 3-borono-4- methoxybenzoic acid (0.049 g, 0.25 mmol), CS₂CO₃ (0.081 g, 0.25 mmol). The reaction mixture was stirred and degassed for 5 min, then tetrakis (3.9 mg, 3.3 μmol) was added. The reaction was heated at 85 ⁰C for 16 his. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1 N HCl, the solid was filtered off. The filtrate two phases were separated and the organic phase was washed with sat. NaCl, dried over anhydrous Na₂S O₄, filtered and concentrated to yield compound 5 (0.056 g, 0.13 mmol, 76 % yield) as a yellow solid. Compound 5 was used without further purification. LC/MS m/z 419 (M+H)⁺ 420.21, RT = 1.478 min [Phenomenex Luna C18 3.0 x 50 mm -- 2 min gradient from 0-100% B, (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)].

Step 6: Preparation of compound 6. To a solution of compound S (0.055 g, 0.13 mmol) in DMF (I mL) was added EDC (0.038 g, 0.20 mmol), HOBT (0.030 g, 0.20 mmol), 2-phenylρropan-2-amine (0.018 g, 0.13 mmol) and DIEA (0.07 mL, 0.39 mmol). The reaction mixture was stirred at 50 ⁰C for 16 hrs. The reaction mixture was diluted in MeOH, filtered and purified by purified by reverse phase prep-HP LC. Fractions from main peak were evaporated in the SpeedVac to yield compound 6 in mono TFA salt form (0.022 %, 0.033 mmol, 25.01 % yield) as a yellow solid. LC/MS m/z 536 (M+H)⁺ 537.40 , RT - 2.86 min; IH NMR (400 MHz, CHLOROFORM-D) ppm 9.46 (1 H, s), 8.04 (1 H, d, 7=9.32 Hz), 7.93 (1 H, dd, J-9.32, 1.51 Hz), 7.81 (1 H, dd, ./=8.56, 2.27 Hz), 7.77 (1 H₅ d, J-2.27 Hz), 7.68 - 7.73 (2 H, m), 7.41 - 7.45 (2 H, m), 7.29 - 7.34 (2 H, m), 7.19 - 7.26 (3 H, m) 7.01 (1 H, d, J-8.56 Hz)₅ 6.63 (1 H, s), 6.42 (1 H, d, J-4.78 Hz), 3.87 (3 H, s), 2.89 (3 H, d, J=4.78 Hz), 1.78 - 1.82 (6 H, m). 2-(4-fluorophenyl)-N-methyI-6-(2-methyl-5-(l-(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)ϊmidazo[l,2-a]pyridine-3-carboxamide (8)

Step 1 : Preparation of compound 7. To a solution of compound 4 (0.12 g, 0.33 mmol) in dioxane (1 mL) and water (0.2 mL) was added 4-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (0.13 g, 0.50 mmol), CS₂CO₃ (0.16 g, 0.50 mmol). The reaction mixture was stirred and degassed for 5 min, then tetrakis (7.7 mg, 6.7 μmol) was added. The reaction mixture was heated at 85 ⁰C for 3 hrs. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1 N HCl, the solid was filtered off. The filtrate two phases were separated and the organic phase was washed with sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield compound 7 (0.050 g, 0.12 mmol, 36 % yield) as a yellow solid. The crude product was used without further purification. LC/MS m/z 403 (M+H)⁺ 404.2, RT = 1.54 min [Phenomenex Luna Cl 8 3.0 x 50 mm ~ 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)]. Step 2: Preparation of compound 8. To a solution of compound 7 (0.050 g, 0.12 mmol) in DMF (1 mL) was added EDC (0.036 g, 0.19 mmol), HOBT (0.028 g, 0.19 mmol), l-(pyridin-2-yl)cyclopropanamme (0.020 g, 0.15 mmol) and DIEA (0.087 mL, 0.50 mmol). The reaction mixture was stirred at 50 ⁰C for 16 hrs. The reaction mixture was diluted in MeOH, filtered and purified by purified by reverse phase prep-HPLC. Fractions from main peak were evaporated in SpeedVac to yield compound 8 mono TFA salt (0.022 g, 0.029 mmol, 24 % yield) as a white solid. LC/MS m/z 519 (M+H)⁺ 520.34, RT = 1.99 min; IH NMR (400 MHz₁ CHLOROFORM-D) ppm 9.96 (1 H, s), 9.40 (1 H, s), 8.64 (1 H₅ d_} J=5.54 Hz), 8.27 - 8.35 (1 H, m), 8.12 (1 H, d, J=9.32 Hz), 7.99 (1 H, d, J=8.06 Hz), 7.87 (1 H, dd, 7=8.06, 1.76 Hz), 7.82 (1 H, s), 7.68 - 7.79 (4 H, m), 7.37 (1 H, d, J=8.06 Hz)₅ 7.25 - 7.30 (2 H, m), 6.01 (1 H, d, J=4.53 Hz), 2.87 (3 H, d, /=5.04 Hz), 2.32 (3 H, s), 1.59 - 1.66 (2 H, m), 1.49 - 1.56 (2 H, m).

6-(2-chloro-5-(2-phenylpropan-2-ylcarbamoyl).phenyl)-2-(4-fluorophenyl)-N- methylimidazo(l,2-a]pyridme-3-carboxamide (10)

Step 1 : Preparation of compound 9. To a solution of compound 4 (0.058 g_> 0.17 mmol) in dioxane (1 mL) and water (0.200 mL) was added 3-borono-4-chlorobenzoic acid (0,050 g, 0.25 mmol), CS₂CO₃ (0.081 g, 0.25 mmol). The reaction mixture was stirred and degassed for 5 min, then tetrakis (4 mg, 3 μmol) was added. The reaction mixture was heated at 85 ⁰C for 3 hrs. The reaction mixture was cooled to rt, diluted with EtOAc, washed with 1 N HCl, the solid was filtered off. The filtrate two phases were separated and the organic phase was washed with sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield compound 9 (0.074 g, 0.175 mmol) as a yellow solid. The crude product was used without further purification. LC/MS m/z 423 (M+H)⁺ 424.22, RT = 1.65 min [Phenomenex Luna C18 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOHZH₂OZTFA)].

Step 2: Preparation of compound 10. To a solution of compound 9 (0.074 g, 0.17 mmol) in DMF (1 mL) was added EDC (0.050 g, 0.26 mmol), HOBT (0.040 g, 0.26 mmol), 2-phenylpropan-2-amine (0.024 g, 0.18 mmol) and DIEA (0.091 mL, 0.52 mmol). The reaction mixture was stirred at 50 ⁰C for 16 hrs. The reaction mixture was diluted in MeOH₉ filtered and purified by purified by reverse phase prep-HPLC. Fractions from main peak were evaporated to yield a clear oil. The oil was dissolved in methylene chloride and charged to a 4 g silica gel cartridge which was eluted with a 15 min gradient of 0-100% EtOAc in hexane. The fractions containing the desired product were concentrated to yield compound 10 (0.022 g, 0.040 mmol, 22 % yield) as a white solid. LC/MS m/z 540 (M+H)⁺ 541.27, RT - 1.91 min [Phenomenex Luna C18 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)]; IH NMR (500 MHz, CHLOROFORM-D) ppm

9.50 (1 H, s), 7,80 (1 H, d, /=2.14 Hz), 7.73 (1 H, dd, J=8.39, 2.29 Hz), 7.66 - 7.70 (3 H, m), 7.53 (1 H, d, J=8.24 Hz), 7.42 - 7.46 (3 H, m), 7.33 (2 H, t, MJ.63 Hz), 7.17 - 7.26 (3 H, m), 6.59 (1 H, s), 5.77 (1 H, d, J=4.58 Hz), 2.84 (3 H, d, J=4.58 Hz), 1.81 (6 H, s). 2~(4-fluorophenyl)~N-raethyl-6-(2-methyI-5-(2-phenylpropan-2- ylcarbamoyϊ)phenvl)imidazo[l,2~a]pyridine-3-carboxamide (11)

Step 1: Preparation of compound 11. To a solution of compound 7 (0.050 g, 0.12 mmol) in DMF (1 mL) was added EDC (0.036 g, 0.19 mmol), HOBT (0.02S g, 0.19 mmol), 2-phenylpropan-2-amine (0.017 g, 0.12 mmol) and DIEA (0.065 mL, 0.37 mmol). The reaction mixture was stirred at 50 ⁰C for 16 hrs. The reaction mixture was diluted in MeOH, filtered and purified by reverse phase prep-HPLC. Fractions from main peak were evaporated to yield a clear oil. The oil was dissolved in methylene chloride and charged to a 4 g silica gel cartridge which was eluted with a 15 min gradient of 0-100% EtOAc in hexane. The fractions containing the desire product were combined and concentrated to yield compound 11 (0.015 g, 0.029 mmol 23 % yield) as a white solid. LC/MS m/z 520 (M+H)⁺ 521.38, RT = 2.91 min; IH NMR (500 MHz, CHLO ROFORM-D) ppm 9.42 (1 H, s), 7.66 - 7.73 (5 H, m), 7.45 (2 H, d, /-7.32 Hz), 7.31 - 7.37 (4 H, m), 7.19 - 7.24 (3 H₅ m), 6.46 (1 H₅ s), 5.74 (1 H, d, 7=4.58 Hz), 2.85 (3 H₁ d, J=4.88 Hz), 2.34 (3 H, s), 1.82 (6 H, s).

trans-2-(4-fluorophenyl)-N-methyl-6-((lS,2R)-2-(l-(pyridin-2- yl)cycIopropylcarbamoyI)cyclopropyl)imidazo[l,2-a]pyridine-3-carboxamide and cis-2-(4-fluoropheπyl)-N-methyl-6-((lS,2R)-2-(l-(Py^ridin-²- yl)cyclopr opylcarbamoyl)cy clopr opyl)imidazo [ 1 ,2-a] pyriditie-3-carb ox amide

Pd(OAc)₂, ether

13

14

compounds 15 and 16

Step 1: Preparation of compound 12, To a solution of 4,4,5, 5-tetramethyl-2-vinyl- 1,3,2-dioxaborolane (0.31 g_} 2.0 mmol) and PdOAc₂ (4.5 mg, 0.02 mmol) in anhydrous Ether (3 mL) was added a solution of ethyl 2-diazoacetate (0,57 g, 5.0 mmol) in ether (2 mL) dropwise under N₂. During the halfway of the addition, additional PdOAc₂ (4.49 mg, 0.02 mmoi) was added. When N₂ evolution had ceased, the reaction mixture was filtered through activated neutral aluminum oxide and washed with ether. The filtrate was concentrated to yield compound 12 (0.50 g, 2.0 mmol) as a yellow oil. The crude product was used without further purification.

Step 2: Preparation of compound 13. To a stirring degassed solution of compound 4 (0.060 g, 0.17 mmol), compound 12 (0.083 g, 0.35 mmol) and potassium carbonate (0.119 g, 0.862 mmol) in DME (2 mL) under Ar was added PdCl₂(dppi> CH₂Cl₂AdUuCt (4 mg, 5 μmol) and water (0.2 mL). The reaction mixture was heated to 85 ⁰C for 4 hrs. The reaction mixture was cooled to rt, diluted with EtOAc, washed with sat. NaHCO₃, sat. NaCl, filtered and concentrated to yield a yellow solid. The solid was dissolved in methylene chloride and charged to a 12 g silica gel cartridge which was eluted with a 20 min gradient of 0-100% EtOAc in hexane. The fractions containing the desired product were concentrated to yield diastereomer mixture of compound 13 (0.036 g, 0.094 mmol, 55 % yield) as a yellow solid.

LC/MS m/z 381 (M+H)⁺ 382.3, RT = 1.91 min; LC/MS m/z 381 (M+H)⁺ 382.3, RT = 2.14 min.

Step 3: Preparation of compound 14. A solution of compound 13 (0.036 g, 0.094 mmol) in THF (1 mL) and MeOH (0.250 mL) was added 10 N NaOH (0.028 mL, 0.28 mmol). The reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated. The residue was diluted with EtOAc, washed with 5% citric acid, sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield diastereomer mixtures of compound 14 (0.033 g, 0.093 mmol) as a yellow solid. The crude product was used without further purification. LC/MS m/z 353 (M+H)⁺ 354.26, RT - 1.497 min; LC/MS m/z 353 (M+H)⁺ 354.26, RT = 1.663 min.

Step 4: Preparation of compound IS and 16. To a solution of compound 14 (0.033 g, 0.093 mmol) in DMF (2 mL) was added EDC (0.036 g, 0.19 mmol), HOBT (0.029 g, 0.19 mmol), DIEA (0.13 mL, 0.75 mmol) and 1 -pyridin-2-yl-cyclopropylamine 3HCl salt (0.025 g, 0,19 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was dissolved in MeOH, filtered and purified by reverse phase prep- HPLC. The diastereomer mixtures were separated on prep HPLC. Fractions from main peak were evaporated in SpeedVac to yield compound 15 2TFA salt (0.008 g, 0.011 mmol, 12 % yield) as a white solid. LC/MS m/z 469 (M+H)⁺ 470.28, RT = 1.44 min; IH NMR (400 MHz, MeOD) ppm 8.82 (1 H, s), 8.23 (1 H, d, /-5.04 Hz), 7.68 - 7.74 (2 H, m), 7.46 - 7.55 (2 H, m), 7.19 - 7.29 (3 H, m), 6.96 (1 H, dd, J=7.43, 4.91 Hz), 6.91 (1 H, d, J=8.06 Hz), 2.81 - 2.85 (3 H, m), 2.64 (1 H, q, J=8.23 Hz), 2.25 (1 H, td, /=8.37, 5.67 Hz), 1.70 - 1.79 (1 H, m), 1.26 - 1.48 (3 H, m), 1.06 - 1.15 (1 H, m), 0.85 - 0.95 (1 H, m); and compound 16 in bis-TFA salt form (0.008 g, 0.011 mmol, 12 % yield) as a white solid. LC/MS m/z 469 (M+H)⁺ 470.28, RT - 1.61 min; IH NMR (400 MHz, MeOD) ppm 8.97 (1 H, s), 8.58 (1 H, dd, J=ό.O4, 1.51 Hz), 8.34 (1 H, td, J=7.93, 1.76 Hz), 7.79 - 7.85 (1 H, m), 7.71 - 7.78 (5 H, m), 7.32 - 7.38 (2 H, m), 2.86 - 2.90 (3 H, m), 2.59 - 2.67 (1 H, m), 2.13 - 2.20 (1 H, m), 1.68 - 1.76 (2 H₅ m), 1.60 - 1.66 (1 H, m), 1.54 - 1.59 (2 H, m), 1.47 (1 H, ddd, J=8.56, 6.30, 4.78 Hz).

2-(4-fluorophenyl)-6-(3-(isobutylcarbamoyl)-4-{pyridin-3-yI)phenyϊ)-N- methylimidazo[l,2-a]pyridine-3~carboxaιmde (19)

17

Step 1 : Preparation of compound 17. To a solution of compound 4 (0.10 g, 0.29 mmol) in dioxane (1 mL) and water (0.2mL) was added 5-borono-2-chlorobenzoic acid (0.087 g, 0.44 mmol), CS₂CO₃ (0.14 g, 0.44 mmol). The reaction mixture was stirred and degassed for 5 min, then tetrakis (7 mg, 6 μmol) was added. The reaction mixture was heated at 85 ⁰C for 3 hrs. The reaction mixture was cooled to rt, diluted with EtOAc. The organic phase was washed with 1 N HCl, sat. NaCl, dried over anhydrous Na₂SO4, filtered and concentrated to yield compound 17 as a pale yellow solid. The crude product was used without further purification. LC/MS m/z 423 (M+H)⁺ 424.10, RT - 2,40 min. Step 2: Preparation of compound 18. To a solution of compound 17 (0.12 g, 0.28 ramol) in DMF (2 mL) was added EDC (0.081 g, 0.43 mmol)_> HOBT (0.065 g, 0.43 mmol), DIEA (0.15 mL, 0.85 mmol) and isobutylamine (0.042 mL, 0.43 mmol). The reaction mixture was stirred at 50 ⁰C for 2 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3, sat. NaCl, dried over anhydrous Na₂SO^ filtered and concentrated to yield a pale yellow solid. The solid was suspended in methylene chloride and charged to a 40 g silica gel cartridge which was eluted with a 20 min gradient of 0- 15% MeOH in CH₂CI₂. The fraction containing the desired product was concentrated to yield compound 18 (0,050 g, 0.10 mmol, 37 % yield) as a pale yellow solid. LC/MS m/z 478 (M+H)⁺ 479.26, RT - 2.66 min.

Step 3: Preparation of compound 19. To a microwave vial was added compound 18 (0.050 g, 0.104 mmol), pyridin-3-ylboronic acid (0.038 g, 0.313 mmol), Pd(OAc)₂ (4.69 mg, 0.021 mmol), 2-dicyclohexylphosphino-2^!,6'-dimethoxybiphenyl (8.57 mg, 0.021 mmol), potassium phosphate, tribasic (0,089 g, 0.418 mmol), dioxane (1 mL) and Water (0.100 mL). The reaction mixture was degassed and filled with N₂. The reaction mixture was heated at 130 ⁰C in microwave reactor for 15 min. The reaction mixture was diluted with EtOAc, washed with sat. NaHCθ₃, sat. NaCl, dried over anhydrous Na₂SO^ filtered and concentrated to yield a yellow residue. The residue was dissolved in MeOH and DMF, filtered and purified by reverse phase prep HPLC Fractions from main peak were evaporated to yield a white solid. The solid was dissolved in methylene chloride and CHCI₃ and charged to a 4 g silica gel cartridge which was eluted with a 20 min gradient of 0-15% MeOH in CH₂Cl₂. The fraction containing the desired product was concentrated to yield compound 19 (0.004 g, 7 μmol, 6 % yield) as a white solid. LC/MS m/z 521.58 (M+H)⁺ 522.25, RT - 2.05 min; IH NMR (400 MHz, CHLOROFORM-rf) ppm 9.77 (1 H, s), 8,72 (1 H, br. s.), 8.62 (1 H, br. s.), 7.88 (1 H, d, J=2.01 Hz)₅ 7.86 (1 H, d, J=8.06 Hz), 7.74 - 7.81 (2 H₅ m), 7.65 - 7.73 (3 H₅ m), 7.47 (1 H, d, J=8.06 Hz), 7.39 (1 H, dd, /-7.55, 5.04 Hz), 7.19 - 7.24 (2 H₅ m), 5.78 (1 H, br. β.), 5.61 (1 H, t, J=5.79 Hz), 3.07 (2 H, t, J=6.42 Hz), 2,88 (3 H, d, J=4.78 Hz), 1.60 (1 H, dt, /=13.41, 6.77 Hz)_} 0.68 - 0.76 (6 H, m). 2~(4-fluørophenyI)-6-(2-(isobutylearbamoyl)biphenyl-4-yI)-N- methyHmidazo[l,2-a]pyridine-3-carboxamide(20)

Step 1 : Preparation of compound 20. To a microwave vial was added compound 18 (0.030 g, 0.063 mmol), phenylboronic acid (0.023 g, 0.19 mrnol), PdOAc₂ (3 mg, 0.01 mmol), 2-dicyclohexylphosphino-2'_?6ⁱ-dimethoxybiphenyl (5 mg, 0.01 mmol), potassium phosphate, tribasic (0.053 g, 0.25 mmol), dioxane (1 mL) and water (0.1 mL). The reaction mixture was degassed and filled with N₂. The reaction mixture was heated at 130 ⁰C in microwave reactor for 15 min. The reaction mixture was diluted with EtOAc, washed with sat. NaHCOj, sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield a yellow solid. The solid was dissolved in MeOH and DMF, filtered and purified by reverse phase prep HPLC. Fractions from main peak were evaporated via SpeedVac to yield compound 20 mono TFA salt (0.024 g, 0.036 mmol, 58 % yield) as a white solid. LC/MS m/z 520 (M+H)⁺ 521.12, RT = 2.88 min; IH NMR (400 MHz, MeOD) ppm 9.39 (1 H, s), 8.31 (1 H, dd, J=9.32, 1.51 Hz), 7.98 (1 H, d, /-9.32 Hz), 7.88 (1 H, dd, J=8.06, 2.01 Hz), 7.76 - 7.85 (3 H, m), 7.60 (1 H, d, J=8.06 Hz), 7.45 - 7.51 (2 H, m), 7.32 - 7.45 (5 H, m), 2.96 - 3.00 (2 H, m), 2.89 (3 H, s), 1.63 (1 H, dt, J=I 3.53, 6.70 Hz), 0.71 (6 H, d, J=6.80 Hz).

6-(2'-chloro-2-(isobutylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N- methylimidazo[l,2-a]pyndine-3-carboxamMe (21)

Step 1 : Preparation of compound 21

To a microwave vial was added compound 18 (0.030 g, 0.063 mmol), 2- chlorophenylboronic acid (0.029 g, 0.19mmol), PdOAc₂ (2.8 mg₅ 0.01 mmol), 2- dcyclohexylphosphino-2^I,6^t-dimethoxybiphenyl (5 nig, 0.01 mmol), potassium phosphate, tribasic (0.053 g, 0.25 mmol), doxane (1 niL) and water (0.1 mL). The reaction mixture was degassed and filled with N₂. The reaction mixture was heated at 130 ⁰C in microwave reactor for 15 min. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO₃, sat. NaCl, dried over anhydrous Na₂SO,*, filtered and concentrated to yield a yellow solid. The solid was dissolved in MeOH and DMF, filtered and purified by reverse phase prep HPLC. Fractions from main peak were evaporated via SpeedVac to yield a yellow residue. The residue was dissolved in methylene chloride and charged to a 4 g silica gel cartridge which was eluted with a 15 min gradient of 0-100% EtOAc in hexane. The fraction containing the desired product was concentrated to yield compound 21 (0.003 g, 4 μmol, 6 % yield) as a white solid. LCMS m/z 554 (M+H)⁺ 555.15, RT = 3.16 min; IH NMR (400 MHz, MeOD) ppm 9.27 (1 H, s) 7.84 - 7.92 (3 H, m) 7.73 - 7.80 (3 H_s m) 7.38 - 7.48 (3 H, m) 7.32 - 7.37 (2 H, m) 7.21 - 7.29 (2 H, m) 3.00 (2 H, d, /-6.80 Hz) 2.87 (3 H, s) 1.61 - 1.66 (1 H, m) 0.77 (7 H, d, J=6.8O Hz).

6-(2-chioro-4-methoxy-5-(l-(pyridin-2-yl)cyclopropyIcarbamoyI)phenyI)-2-(4- fluor ophenyl)-N-raethylimidazo [1,2-a J pyr idine-3-car b oxamide (23)

22

23

Step 1 : Preparation of compound 22. To a solution of compound 4 (0.040 g, 0.12 mmol) in dioxane (2 mL) and water (0.4 mL) was added 5-borono-4-chloro-2- methoxybenzoic acid (0.040 g, 0.17 mmol), CS₂CO₃ (0.056 g, 0.17 mmol). The reaction mixture was stirred and degassed for 5 mill, then tetrakis (3 mg, 3 μmol) was added. The reaction mixture was heated at 85 ⁰C for 3 hrs. The reaction mixture was cooled to rt, diluted with EtOAc and the organic phase was washed with 5% citric acid, sat. NaCl, dried over anhydrous NaJSO₄, filtered and concentrated to yield compound 22 (0.052 g, 0.12 mmol) as a pale yellow solid. The crude product was used without further purification. LC/MS m/z 453 (M+H)⁺ 454.10, RT = 2.37 min.

Step 2: Preparation of compound 23. To a solution of compound 22 (0.052 g, 0.12 mmol) in DMF (1 mL) was added l-(pyridin-2-yl)cyclopropaπamme 2hydrochloride (0.020 g, 0.12 mmol), EDC (0.022 g, 0.12 mmol), HOBT (0.018 g, 0.12 mmol) and DIEA (0.080 mL, 0.46 mmol). The reaction mixture was stirred at rt. The reaction mixture was dissolved in MeOH, filtered and purified by reverse phase prep HPLC. Fractions from main peak were evaporated in SpeedVac to yield clear oil. The oil was dissolved in methylene chloride and charged to a 4 g silica gel cartridge which was eluted with a 20 min gradient of 0-15% MeOH in CH₂Cl₂. The fraction containing the desired product was concentrated to yield compound 23 (0.006 g, 10 μmol, 9 % yield) as a white solid. LC/MS m/z 569 (M+H)⁺ 570.01, RT - 2.206 min; IH NMR (400 MHz, MeOD) d ppm 9.00 (1 H, s), 8.40 (1 H, d, J= 4.03 Hz), 7.90 (1 H, s)_} 7.73 - 7.78 (2 H, m), 7.66 - 7.73 (2 H, m), 7.52 - 7.60 (2 H, m), 7.41 (1 H, s), 7.21 - 7.27 (2 H, m), 7.15 (1 H, ddd, J- 7.43, 4.91, 1.26 Hz)₉ 4.06 (3 H, s), 2.82 (3 H, s), 1.63 - 1.68 (2 H, m), 1.34 - 1.38 (2 H, m).

2-(4-fluorophenyl)-N,7-dimethyl-6-(2-methyl-5-(2-phenylρropan-2- ylcarbamoyl)phenyl)imidazo[l,2-a]pyridine-3-carboxaimde (28)

27

28

Step 1 : Preparation of compound 24. To a solution of compound 1 (3 g, 12.8 mmol) in ethanol (16 mL) was added 5-chloro-4-methylpyridin-2-amine (2 g, 14.0 mmol), the reaction mixture was stirred at 70 ⁰C under N₂ for 16 hrs. The reaction mixture was diluted in EtOAc, washed with sat. NaHCO₃, water and sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield yellow oil. The oil was dissolved in DCM and charged to a 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-80% EtOAc in hexane. The fractions containing the desired product were concentrated to yield compound 24 (i.2 g, 3.5 mmol, 27 % yield) as a white solid. LC/MS m/z 332 (MH-H)⁺ 333, RT = 1.96 min [Phenomenex Luna Cl 8 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)].

Step 2: Preparation of compound 25. To a solution of compound 24 (0.8 g, 2.4 mmol) in THF (8 mL) and MeOH (2 mL) was added 1 N NaOH (6 mL₅ 6 mmol). The reaction mixture was stirred at 45 ⁰C for 2 hrs. The reaction mixture was cooled to rt and concentrated to remove most solvent. The reaction residue was acidified with 1 N HCl, the white solid precipitated. The solid was filtered and dried to yield compound 25 (0.58 g, 1.9 mmol, 79 % yield) as a white solid. LC/MS m/z 304 (M+H)⁺ 305.1, RT = 1.58 min [Phenomenex Luna C18 3.0 x 50 mm - 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/MeOH/TFA; B: 90/10/0.1 MeOHZH₂CVTFA)] .

Step 3: Preparation of compound 26. To a solution of compound 25 (0.58 g, 1.9 mmol) in DMF (5 mL) was added EDC (0.55 g, 2.9 mmol), HOBT (0.44 g, 2.9 mmol), methylamine hydrochloride (0.26 g, 3.8 mmol) and DIEA (1.0 mL, 5,7 mmol). The reaction mixture was stirred at 50 ⁰C for 2 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO₃, sat. NaCl, dried over anhydrous Na₂SO₄, filtered and concentrated to yield compound 26 (0.60 g, 1.9 mmol) as a yellow solid. The crude product was used without further purification. LC/MS m/z 317 (M+H)⁺ 318.11, RT - 1.257 min [Phenomenex Luna C18 3.0 x 50 mm -- 2 min gradient from 0-100% B. (A: 90/10/0.1 H₂O/Me0H/TFA; B: 90/10/0.1 MeOH/H₂O/TFA)].

Step 4: Preparation of compound 27. To a microwave vial was added compound 26 (0.030 g, 0.09 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoic acid (0.025 g, 0.09 mmol), PdOAc₂ (4 mg, 0.02 mmol), 2- dicyclohexylphosphino~2',6'-dimethoxybiphenyl (8 mg, 0.02 mmol), potassium phosphate, tribasic (0.060 g, 0,3 mmol), dioxane (1 mL) and water (0.1 mL). The reaction mixture was degassed and filled with N₂. The reaction mixture was heated at 130 ⁰C in microwave reactor for 15 min. The reaction residue was dissolved in MeOH and DMF, filtered and purified by reverse phase prep HPLC. Fractions from main peak were evaporated via SpeedVac to yield compound 27 (0,040 g, 0.09 mmol, 100 % yield) as a white solid. LC/MS m/z 417 (M+H)⁺ 418.35, RT = 2.35 min.

Step 5: Preparation of compound 28. To a solution of compound 27 (0.040 g, 0.09 mmol) in DMF (8 mL) was added o-benzotriazol-l-yl-N,N,N',N'-tetramethyluromum tetrafluoroborate (0.058 g, 0.18 mmol) and TEA (0.033 mL, 0.24 mmol) and 2- phenylpropan-2-amine (0.016 g, 0.12 mmol). The reaction mixture was stirred at it for 16 hrs. The reaction mixture was diluted in MeOH, filtered and purified by reverse phase prep HPLC. Fractions from main peak were evaporated overnight in SpeedVac to yield compound 28 mono TFA salt (0.012 g, 0.018 mmol, 15 % yield) as a white solid. LC/MS m/z 534 (M+H)⁺ 535.19, RT = 2.79 min; IH NMR (400 MHz, MeOD) ppm 8.90 (1 H, s), 7.87 (1 H_} dd, J=8.06, 1.76 Hz), 7.83 (1 H, s), 7.76 - 7.81 (2 H, m), 7.64 (1 H, d, /=2.01 Hz), 7.49 (1 H, d, J=8.06 Hz), 7.33 - 7.44 (4 H, m), 7.23 - 7.30 (2 H, m), 7.11 - 7.18 (1 H, m), 2.79 - 2.85 (3 H, m), 2.28 (3 H, s), 2.19 (3 H, s), 1.73 (6 H, s).

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

CLAIMSWe claim:

1. A compound of formula I, II, III, IV, or V

where:

_R9 _R10

CONR⁷R⁸ ₍ piperidinonyl substituted with 1 ^{* Ap1} substituent, pyrrolyl

R⁹ R¹⁰ substituted with 1 ^{* Ap1} substituent, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents;

R² is hydrogen, halo, alkyl, cycloalkyl, alkoxy, or R⁵R⁶N;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, benzyl, alkylcarbonyl, haloalkylcarbonyl, phenylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, phenylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl;

R is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

R³ R¹⁰ R⁹ R¹⁰ R⁷ is hydrogen, alkyl, ^^R15 , or *^^Ar¹ .

R⁸ is hydrogen or alkyl;

R is hydrogen or alkyl;

R » 10 ; is hydrogen or alkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen or alkyl; or R¹ ' and R¹² taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R^B is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

R¹⁵ is alkyl or cycloalkyl;

R^lϋ is hydrogen, halo, alkyl, or alkoxy;

R¹⁷ is hydrogen, halo, alkyl, or alkoxy; and

or a pharmaceutically acceptable salt therof.

2. A compound of claim 1 where

R¹ is halo, alkoxy, oxazolidinonyl, dioxothiazinyl, R⁵R⁶N, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyϊ, alkoxyalkyl, and CONR⁷R⁸, and where said phenyl is substituted with 0-1 alkyl substituents;

R² is hydrogen, halo, alkoxy, or R⁵R⁶N;

R³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl, (alkylsulfonyl)aminocarbonyl, CONR¹¹R¹², (R¹³)(R^l4)NCONH, triazolyl, thiazolyl, or tetrazolyl; R⁴ is phenyl substituted with 0-2 halo;

R⁵ is alkylsulfonyl;

R^fi is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

R⁹ R¹⁰ R⁷ is hydrogen, alkyl, or ^*^^Ar¹

R is hydrogen or alkyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen or alkyl;

R^u is hydrogen or alkyl;

R¹² is hydrogen or alkyl;

R¹³ is hydrogen oτ alkyl;

R¹⁴ is hydrogen or alkyl;

or R¹³ and R¹⁴ taken together with the nitrogen to which they are attached is azetidinyl, pyrroiidinyl, piperidinyl, piperazinyl, or morpholinyl;

R¹⁵ is hydrogen;

R¹⁷ is hydrogen; and

Ar¹ is phenyl or pyridmyl; or a pharmaceutically acceptable salt therof.

3. A compound of claim 1 where

R¹ is alkoxy or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 alkyl substituents;

R² is hydrogen, halo or R⁵R^ύN;

R³ is CONR¹³R'⁴;

R⁴ is phenyl substituted with 0-2 halo;

R⁵ is alkylsulfonyl;

R^δ is hydrogen or hydroxyalkyl;

R⁹ R¹⁰

R⁷ is hydrogen, alkyl, or * ^Ar1 ;

R⁸ is hydrogen;

R⁹ is alkyl;

R • t^Io^U is alkyl;

or R⁹ and R¹⁰ taken together is ethylene or propylene;

R¹¹ is hydrogen or alkyl;

R is hydrogen or alkyl; R^!3 is hydrogen or alkyl;

R¹⁴ is hydrogen or alkyl;

or R¹³ and R¹⁴ taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or raorpholinyl;

R¹⁵ is hydrogen;

R¹⁷ is hydrogen; and

Ar¹ is pyridinyl or phenyl, and is substituted with 0-1 alkyl or phenyl substituents;

or a pharmaceutically acceptable salt therof.

4. A compound of claim 1 where

R¹ is cycloalkyl, alkoxy, CONR⁷R⁸ _} piperidinonyl substituted with 1

R⁹ R¹⁰ R⁹ R¹⁰

* ^Ar1 substituent, pyrrolyl substituted with 1 ^{* Af1} substituent, or phenyl where said phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, carboxy, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents;

R² is hydrogen, halo, cycloalkyl, or R⁵R⁶N;

R³ is CONR^πR¹²;

R⁴ is phenyl substituted with 0-2 halo; R⁵ is hydrogen, (cycloalkyl)alkyl, benzyl, haloalkylcarbonyl, (alkoxyphenyl)carbonyl, alkylsulfonyl, (alkoxyphenyl)sulfonyl or (haloalkoxyphenyl)sulfonyl;

R⁶ is hydrogen or hydroxyalkyl;

_D9 _R10 _R9 _R10

R⁷ is hydrogen, alkyl, *^R¹⁵ , or * Ar¹ .

R is hydrogen;

R⁹ is alkyl;

R , 1^ι0^υ is alkyl;

or R and R _> io taken together is ethylene or propylene;

R »π" is alkyl;

R¹² is hydrogen;

R¹³ is alkyl or cycloalkyl;

R¹⁶ is hydrogen;

R¹⁷ is hydrogen; and

or a pharmaceutically acceptable salt therof.

5. A compound of claim 1 where R^! is phenyl substituted with 1 CONR⁷R⁸ substituent and 0-2 halo, alkyl, or alkoxy substituents; R² is hydrogen, halo, alkyl, or R⁵R⁶N; R³ is CONR¹¹R¹²; R⁴ is moiioflurophenyl; R⁵ is alkylsulfonyl; R⁶ is alkyl; R⁷

_R9 _Ri0 is ^{* Al"1} ; R⁸ is hydrogen; R⁹ is methyl; R¹⁰ is methyl; or R⁹ and R¹⁰ taken together is ethylene; R^u is alkyl; R¹² is hydrogen or alkyl; R^lβ is hydrogen; R¹⁷ is hydrogen; and Ar¹ is oxadiazolyl, pyridinyl, pyrimidinyl, or phenyl, and is substituted with 0-1 halo or alkyl substituents; or a pharmaceutically acceptable salt therof.

6. A compound of claim 1 where R¹ is phenyl substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxy, and CONR⁷R⁸, and where said phenyl is also substituted with 0-2 halo, alkyl, alkoxy, pyridinyl, phenyl or halophenyl substituents.

7. A compound of claim 1 where R¹ is phenyl is substituted with 1-2 substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and CONR⁷R⁸, and where said phenyl is substituted with 0-1 halo, alkyl, or alkoxy substituents.

8. A compound of claim 1 selected from the group consisting of

4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5 -( 1 - ρhenylcycloρroρylcarbamoyl)phenyl)~N~methylpyrazolo[l,5-β]ρyridine-3- carboxamide;

4-fiuoro-2-(4-fiuoroρhenyl)-5-(4'-methoxy-2-methyl-5~(l~(pyridin-2- y^cyclopropylcarbamoyOpheny^-N-methylpyrazolo [ 1 ,5 -#]pyridine-3-carboxamide;

2-(4-fluoroρhenyl)-N-methyl-5-(2-methyl-5-( 1 -(pyridin-2- yl)cyclopropylcarbamoyl)phenyl)pyrazolo[l,5-a]pyridine-3-carboxamide;

6-(N-ethylmethylsulfonamido)-2-(4-fluoroρhenyl)-N-methyl-5-(3-(2-phenylpropan- 2-ylcarbamoyl)phenyl)pyrazolo[ 1 ,5-α]pyridine-3-carboxamide; 6-(N-ethy]methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(l-(pyridin-2~ yl)cyclopropylcarbamoyl)phenyl)pyrazolo[ 1 ,5 ~«]pyridine-3-carboxamide;

4-fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5 -( 1 - phenylcyclopropylcarbamoyljpheny^pyrazolof I j5-«]pyridine-3-carboxamide;

4-fluoiO-2~(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(l-(3-methyl-l,2,4-oxadiazol- S-y^cyclopropylcarbamoy^pheny^-N-raethylpyrazolofljS-aJpyridine-S- carboxamide;

4-fluoro-2-(4-fiuorophenyl)-5-(4-methoxy-2-methyl-5-(l-(pyrimidin-2- yl)cyclopropylcarbamoyl)phenyl)-N-methylpyrazolo[l,5-β]pyridine-3-carboxamide;

4-fluoro-2-(4-fluorophenyl)-5-(5-(l-(3~fluorophenyl)cyclopropylcarbamoyl)-4- methoxy-2-methylphenyl)-N-methylpyrazolo[ 1 ,5-α]pyridine-3-carboxamide;

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-( 1 -(pyridin-2- yl)cyclopropylcarbamoyl)ρhenyl)fbro[2,3-έ]pyridine-3-carboxamide; and

5-(2-chloro-5-( 1 -(pyridin-2-yl)cyclopropylcarbamoyl)phenyI)-2-(4-fluorophenyl)-N- methylftiro[2,3-δ]ρyridine-3-carboxamide;

or a pharmaceutically acceptable salt therof.

9. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient.